Ribavirin-interferon alfa combination therapy for eradicating detectable HCV-RNA in patients having chronic hepatitis C infection

ABSTRACT

Ribavirin derivatives represented by the formula II, pharmaceutical compositions containing them as well as methods of using the ribavirin derivatives represented by the formula II for the treatment of susceptible viral infections, for example, chronic hepatitis C infections administrating, the ribavirin derivatives being represented by formula II  
                 
 
     are disclosed.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to ribavirin derivativesrepresented by the formula II, pharmaceutical compositions containingthem as well as methods of using the ribavirin derivatives representedby the formula II for treating susceptible viral infections, forexample, chronic hepatitis C infections administrating, the ribavirinderivatives being represented by formula II

[0002] Chronic infection with hepatitis C virus is an insidious andslow-progressing disease having a significant impact on the quality oflife. It can eventually result in cirrhosis of the liver, decompensatedliver disease and/or hepatocelluar carcinoma.

[0003] Combination treatment with interferon alfa-2b and ribavirin ofpatients with chronic hepatitis C is disclosed by Reichard et al.(TheLancet 1998; 351;83-87; and T. Poynard et al.( The Lancet ,1998, Vol.352, October 31, p 1426-1432). See also J. G. McHutchinson et al. (N.Engl. J. Med.,1998, 339:1485-1492); and G. L. Davis et al. (N. Engl. J.Med., 1998, 339:1493-1499).However, this combination therapy is notalways effective due to side effects associated ribavirin such asribavirin-related hemolysis, and anemia.

[0004] There is a definite need for more potent, safer ribavirinderivatives having fewer side effects for use as monotherapy or incombination with antiviral agents, e.g., interferon-alpha, to treatpatients having susceptible viral infections, e.g., chronic hepatitis Cinfections, in a long-term, effective manner.

SUMMARY OF THE INVENTION

[0005] The present invention provides a method of treating patientshaving chronic hepatitis C infection comprising administering atherapeutically effective amount of a ribavirin derivative of formula Iand a therapeutically effective amount of interferon-alpha for a timeperiod sufficient to eradicate detectable HCV-RNA at the end of saidperiod of administering and to have no detectable HCV-RNA for at least24 weeks after the end of said period of administrating, and wherein theribavirin derivative is represented by formula I:

[0006] wherein at least one of R², R³ or R⁵ is H, R⁶-(W)_(x)-CO—,R⁶-(W)_(x)-CS—(HO)₂PO—,R⁶-(W)_(x)-PO(OH)— or HO—SO₂— and wherein atleast one of R², R³ or R⁵ is not H;

[0007] wherein R⁶ is H, alkyl, alkanoyl, cycloalkyl, heterocylic, aryl,NR^(7a)R^(7b), alkenyl, or alkynyl; or is alkyl, alkanoyl, alkenyl oralkynyl substituted by halo, phenyl, cycloalkyl, NR^(7a)R^(7b), hydroxyor alkoxy;

[0008] or R⁶ is aryl substituted by phenyl, halo, CN, NO₂, OH, R¹⁸,OR¹⁸,CF₃, SH SR^(7a),SOR^(7a),SO₂R^(7a); NR^(7a)R^(7b)CO₂H, CO₂ ⁻M⁺⁻,OM⁺OR^(7a) or S⁻M⁺;

[0009] wherein M⁺ is an alkali metal cation;

[0010] or R⁶ is —(CHR^(7a))_(e)(CH₂)_(f)CO—OR^(7b),

[0011] —(CHR^(7a))_(e)—(CH₂)_(f)—OR^(7b), or—(CHR^(7a))_(e)—(CH₂)_(f)—NR^(7a)R^(7b)

[0012] W is O, NR¹⁸or S;

[0013] R^(7a) is H, alkyl, alkanoyl, aryl or is alkyl, alkanoyl or arylsubstituted by halo phenyl CN, NO₂, OH, CO₂H or alkoxy; and R^(7b) is H,alkyl or aryl or is alkyl or aryl substituted by halo, CN, NO₂, CO₂H, OHor alkoxy;

[0014] or R^(7a) and R^(7b) taken together with N and one of CHR^(7a),NR^(7b), O, S, SO or SO₂ form a five-, six- or seven-membered ring;

[0015] R¹⁷ is H, OR^(7a), NR^(7a)R^(7b), R⁶-(W)_(x)-CO—, R⁶-(W)_(x)-CS—,(HO)₂PO—,

[0016] R⁶-(W)_(x)-PO(OH)—, or HO—SO₂—;

[0017] R¹⁸ is H, aryl, alkyl, or alkyl substituted by OH, halo,NR^(7a)R^(7b), or alkanoyl;

[0018] e=0 to 6, f=0 to 10, and x=0 or 1;

[0019] or a pharmaceutically acceptable salt thereof.

[0020] Preferably R⁵ is R⁶CO wherein R⁶ is aryl substituted by phenyl,halo, CN, NO₂, OH, R¹⁸ ,OR¹⁸, CF₃, SH SR^(7a),SOR^(7a),SO₂R^(7a);NR^(7a)R^(7b)CO₂H, CO₂ ⁻M⁺⁻, O⁻M⁺OR^(7a) or S⁻M⁺. wherein M⁺ is analkali metal cation.

[0021] More preferably R⁵ is R⁶CO wherein R⁶ is phenyl substituted by,halo, CN, NO₂, OH, R¹⁸, OR¹⁸, CF₃, SH SR^(7a),SOR^(7a),SO₂R^(7a);NR^(7a)R^(7b)CO₂H, CO₂ ⁻M⁺⁻, O⁻M⁺OR^(7a) or S⁻M⁺. wherein M⁺ is analkali metal cation.

[0022] The present invention also provides ribavirin derivatives isrepresented by the formula II, pharmaceutical compositions containingthem as well as the use of the ribavirin derivatives represented by theformula II for the preparation of a medicament for the treatment ofsusceptible viral infections, for example chronic hepatitis Cinfections; wherein the pharmaceutical compositions comprising atherapeutically effective amount of a ribavirin derivative of formula Iand a therapeutically effective amount of interferon-alpha, and whereinthe treatment being for a time period of at least 20 to 50 weeks toeradicate detectable HCV-RNA at the end of said 20 to 50 week period oftreatment and to have no detectable HCV-RNA for at least 24 weeks afterthe end of said period of treatment, and wherein the ribavirinderivatives are represented by the formula II:

[0023] wherein at least one of R², R³ or R⁵ is H, R⁶-(W)_(x)-CO—,R⁶-(W)_(x)-CS—(HO)₂PO—,R⁶-(W)_(x)-PO(OH)— or HO—SO₂— and wherein atleast one of R², R³ or R⁵ is not H;

[0024] wherein R⁶ is H, alkyl, alkanoyl, cycloalkyl, aryl, heterocyclic,NR^(7a)R^(7b), alkenyl, or alkynyl;

[0025] or is alkyl, alkanoyl, alkenyl or alkynyl substituted by halo,phenyl, cycloalkyl, NR^(7a)R^(7b), hydroxy, alkoxy;

[0026] or is aryl substituted by phenyl, halo, CN, NO₂, OH, R¹⁸, OR¹⁸,CF₃, SH, SR^(7a),SOR^(7a), SO₂R^(7a); NR^(7a)R^(7b)CO₂H, CO₂ ⁻, OR^(7a),O⁻M⁺ or S⁻M^(+,)

[0027] wherein M⁺ is an alkali metal cation;

[0028] or R⁶ is —(CHR^(7a))_(e)—(CH₂)_(f)—CO—OR^(7b),

[0029] —(CHR^(7a))_(e)—(CH₂)_(f)—OR^(7b), or—(CHR^(7a))_(e)—(CH₂)_(f)—NR^(7a)R^(7b)

[0030] W is O, NR¹⁸ or S;

[0031] R^(7a) is H, alkyl, alkanoyl, or aryl is alky, alkanoyll or arylsubstituted by halo, CN, NO₂, OH, CO₂H or alkoxy;

[0032] and R^(7b) is H, alkyl or aryl or is alkyl or aryl substituted byhalo, CN, NO₂, OH, CO₂H or alkoxy;

[0033] or R^(7a) and R^(7b) taken together with N and one of CHR^(7a),NR^(7b), O, S, SO or SO₂ form a five-, six- or seven- membered ring;

[0034] R¹⁷ is H, OR^(7a), NR^(7a)R^(7b), R₆-(W)_(x)-CO—, R⁶-(W)_(x)-CS—,(HO)₂PO—,

[0035] R⁶-(W)_(x)-PO(OH)— or HO—SO₂—;

[0036] R¹⁸ is H, aryl, alkyl, or alkyl substituted by OH, halo,NR^(7a)R^(7b), or alkanoyl;

[0037] e=0 to 6, f=0 to 10, and x=0 or 1;

[0038] or a pharmaceutically acceptable salt thereof.

[0039] Preferably R⁵ is R⁶CO wherein R⁶ is aryl substituted by phenyl,halo, CN, NO₂, OH, R¹⁸,OR¹⁸, CF₃, SH SR^(7a),SOR^(7a),SO₂R^(7a);NR^(7a)R^(7b)CO₂H, CO₂ ⁻M⁺⁻, O⁻M⁺OR^(7a) or S⁻M⁺, wherein M⁺ is analkali metal cation.

[0040] More preferably R⁵ is R⁶CO wherein R⁶ is phenyl substituted by,halo, CN, NO₂, OH, R¹⁸ ,OR¹⁸, CF₃, SH SR^(7a),SOR^(7a),SO₂R^(7a);NR^(7a)R^(7b)CO₂H, CO₂ ⁻M⁺⁻, O⁻M⁺⁻OR^(7a) or S⁻M⁺,wherein M⁺ is analkali metal cation.

[0041] In another embodiment, the present invention relates to acompound represented by formula II

[0042] wherein at least one of R^(2′),R^(3′) or R^(5′) is H,R²⁰-(W)_(x)-CO—, R²⁰-(W)_(x)-CS— or R²⁰-(W)_(x)-PO(OH)—; and wherein atleast one of R^(2′),R^(3′) or R^(5′) is not H;

[0043] wherein R²⁰ is H, alkyl, alkanoyl, cycloalkyl, aryl,heterocyclic, NR²¹R²², alkenyl, or alkynyl;

[0044] or is alkyl, alkanoyl alkenyl or alkynyl substituted by halogen,phenyl, cycloalkyl, NR²¹R²², hydroxy, alkoxy;

[0045] or R²⁰ is aryl substituted by halogen, phenyl, CN, NO₂, OH, R²⁸,OR²⁸, CF₃, SH, SR²¹ SOR²¹,SO₂R²¹; NR²¹R²², CO₂H, CO₂ ⁻—, OR^(21,), O⁻M⁺or S⁻M^(+,)

[0046] wherein M⁺ is an alkali metal cation;

[0047] or R²⁰ is —(CHR²¹)_(e)—(CH₂)_(f)—CO—OR²²,

[0048] —(CHR²¹)_(e)—(CH₂)_(f)—OR²², or —(CHR²¹)_(e)—(CH₂)_(f)—NR²¹R²²

[0049] W is O, NR²⁸ or S;

[0050] R²¹ is H, alkyl, alkanoyl, or aryl, or is alkyl, alkanoyl or arylsubstituted by halo, phenyl, CN, NO₂ OH, CO₂H or alkoxy; and R²² is H,alkyl or aryl or is alkyl or aryl substituted by halo, phenyl, CN, NO₂,OH, CO₂H or alkoxy;

[0051] or R²¹ and R²² taken together with N and one of CHR² , NR², O, S,SO or SO₂ form a five-, six- or seven- membered ring;

[0052] R²⁷ is H ,OR²¹, NR²¹R²², R²⁰-(W)_(x)-CO—, R²⁰-(W)_(x)-CS—,(OH)₂PO—, R²⁰-(W)_(x)-PO(OH)— or HO—SO₂—;

[0053] R²⁸ is H, aryl, alkyl, or alkyl substituted by OH, halo, NR²¹R²²,or alkanoyl;

[0054] e=0 to 6, f=0 to 10; and x=0 or 1;

[0055] or a pharmaceutically acceptable salt thereof.

[0056] Preferably R^(5′) is R²⁰CO wherein R²⁰ is aryl substituted byhalogen, phenyl, CN, NO₂, OH, R²⁸, OR²⁸, CF₃, SH, SR²¹ SOR²¹, SO₂R²¹;NR²¹R²², CO₂H, CO₂ ⁻—, OR²¹, O⁻M⁺ or S⁻M⁺;

[0057] wherein M⁺ is an alkali metal cation.

[0058] More preferably R^(5′) is R²⁰CO wherein R²⁰ is phenyl substitutedby halogen, CN, NO₂, OH, R²⁸, OR²⁸, CF₃, SH, SR²¹SOR²¹,SO₂R²¹; NR²¹R²²,CO₂H, CO₂ ⁻—, OR²¹, O⁻M⁺ or S⁻M⁺

[0059] wherein M⁺ is an alkali metal cation.

[0060] In another embodiment, the present invention relates to a methodof treating patients having chronic hepatitis C infection comprisingadministering a therapeutically effective amount of a ribavirinderivative of formula II and a therapeutically effective amount ofinterferon-alpha for a time period sufficient to eradicate detectableHCV-RNA at the end of said period of administering and to have nodetectable HCV-RNA for at least 24 weeks after the end of said period ofadministrating, and wherein the ribavirin derivative is represented byformula II

[0061] wherein at least one of R^(2′),R^(3′) or R^(5′) is H,R²⁰-(W)_(x)-CO—R²⁰-(W)_(x)-CS— or R²⁰-(W)_(x)-PO(OH)—; and wherein atleast one of R²,R³ or R⁵ is not H;

[0062] wherein R²⁰ is H, alkyl, alkanoyl, cycloalkyl, aryl,heterocyclic, NR²¹R²², alkenyl, or alkynyl;

[0063] or is alkyl, alkanoyl alkenyl or alkynyl substituted by halo,phenyl, cycloalkyl, NR²¹R²², hydroxy, alkoxy;

[0064] or R²⁰is aryl substituted by phenyl, halo, CN, NO₂, OH, R²⁸, OR²⁸,CF₃, SH, SR²¹²,SOR²¹, SO₂R2¹; NR²¹R²²CO₂H, CO₂ ⁻—, OR²¹, O⁻M⁺ orS⁻M^(+,)

[0065] wherein M⁺ is an alkali metal cation;

[0066] or R²⁰ is —(CHR²¹)_(e)—(CH₂)_(f)—CO—OR²²,

[0067] —(CH R²¹)_(e)—(CH₂)_(f)—OR²², or —(CHR²¹)_(e)—(CH₂)_(f)—NR²¹R²²

[0068] W is O, NR²⁸ or S;

[0069] R²¹ is H, alkyl, alkanoyl, or aryl or is alkyl, alkanoyl or arylsubstituted by halo, phenyl, CN, NO₂, OH, CO₂H or alkoxy; and R²² is H,alkyl or aryl or is alkyl or aryl substituted by halo, CN, NO₂, OH, CO₂Hor alkoxy;

[0070] or R²¹ and R²² taken together with N and one of CHR²¹ , NR²¹, O,S, SO or SO₂ form a five-, six- or seven- membered ring;

[0071] R²⁷ is H, OR²¹, NR²¹R²² , R²⁰-(W)_(x)-CO—, R²⁰-(W)_(x)-CS—,(HO)₂PO—,

[0072] R²⁰-(W)_(x)-PO(OH)— or HO—SO₂—;

[0073] R²⁸ is H, aryl, alkyl, or alkyl substituted by OH, halo, NR²¹R²²,or alkanoyl;

[0074] e=0 to 6, f=0 to 10, and x=0 or 1;

[0075] or a pharmaceutically acceptable salt thereof.

[0076] Preferably R^(5′) is R²⁰CO wherein R²⁰ is aryl substituted byphenyl, halo, CN, NO₂, OH, R²⁸,

[0077] OR²⁸, CF₃, SH, SR^(212 ,SOR) ²¹,SO₂R2¹; NR²¹R²²CO₂H, CO₂ ⁻—,OR²¹, O⁻M⁺ or S⁻ M⁺, wherein M⁺ is an alkali metal cation;

[0078] More preferably R^(5′) is R²⁰CO R²⁰ is phenyl substituted byhalo, CN, NO₂, OH, R²⁸, OR²⁸, CF₃, SH, SR²¹²,SOR²¹,SO₂R2¹; NR²¹R²²CO₂H,CO₂ ⁻—, OR²¹, O⁻M⁺ or S⁻M⁺, wherein M⁺ is an alkali metal cation;

[0079] The present invention provides a compound represented by formulaIII

[0080] wherein at least one of R^(50′)R^(30′) or R^(20′)is representedby the formula

[0081] wherein the other two of R^(50′)R^(30′) or R^(20′) is representedby H or the formula

[0082] wherein Q is:

[0083] wherein R⁵¹ and R⁵² are independently H, alkyl, alkenyl ,alkynyl, (C₃-C₇)cycloalkyl, arylalkyl, or alkyl, alkenyl, alkynyl,(C₃-C₇)cycloalkyl, arylalkyl, substituted by halo, OH, SH ,CF₃,SR⁵⁷,OR⁵⁷ or NR⁵⁵R⁵⁵ or wherein R⁵¹ and R⁵² taken together with thecarbon atom in (C R⁵¹ R⁵²) form a cyclopropane, cyclobutane,cyclopentane, or cyclohexane.;

[0084] wherein R⁵³ and R⁵⁴ are independently H, alkanoyl, alkyl, aryl,arylalkyl, alkenyl , alkynyl, or alkanoyl, alkyl, aryl, arylalkyl,alkenyl, alkynyl substituted by halo, OH, SH , CF₃, ,SR⁵⁷,OR⁵⁷; or R⁵³and R⁵⁴ are independently

[0085] wherein R⁵⁷ is H, alkyl, alkanoyl, alkenoyl, aryl, arylalkyl,alkenyl, alkynyl, or, alkyl, aryl, arylalkyl, alkenyl, alkynylsubstituted by halo, OH, SH, CF₃, alkanoylthienyl, or alkanoyloxy;

[0086] wherein R⁵⁸ is H, alkyl, aryl, arylalkyl, alkenyl, or alkynyl;

[0087] and q is 0, 1 or 2, and k is 1 or 2;

[0088] or a pharmaceutically acceptable salt thereof.

[0089] In a preferred embodiment, R^(30′) and R^(20′) in the compoundsof Formula III are each H.

[0090] The present invention provides a compound represented by theformula IV

[0091] wherein at least one of R^(50″), R^(30″), R^(20″) is representedby the formula

[0092] and wherein the other two of R^(50″), R^(30″), R^(20″) is H or isrepresented by the formula

[0093] wherein T is a moiety represented by the formulas:

[0094] H₂NCH₂—, H₂NCH₂CH₂—, CH₃CH(H₂N)—, CH₃CH₂CH(H₂N)—,CH₃(CH₂)₂CH(H₂N)—, (CH₃)₂CHCH(H₂N)—, (CH₃)₂CHCH₂CH(H₂N)—,CH₃CH₂CH(CH₃)CH(H₂N)—, PhCH₂CH(H₂N)—, HOOCCH₂CH₂CH(H₂N)—,HOOCCH₂CH(H₂N)—, HSCH₂CH(H₂N)—, CH₃SCH₂CH₂CH(H₂N)—, HOCH₂CH(H₂N)—,,H₂N(CH2)₄ CH(H₂N)—, CH₃CH(OH)CH(H₂N),

[0095] wherein R⁵⁸ and R⁵⁹ are independently H, alkyl, alkenyl ,alkynyl, (C₃-C₇)cycloalkyl, arylalkyl, or alkyl, alkenyl, alkynyl,(C₃-C₇)cycloalkyl, arylalkyl, substituted by halo, OH, SH , CF₃,SR⁶⁰,OR⁶⁰ or NR⁶⁰R⁶¹ or wherein R⁵⁸ and R⁵⁹ taken together with thecarbon atom in (C R⁵⁸ R⁵⁹) form a cyclopropane, cyclobutane,cyclopentane, or cyclohexane.;

[0096] wherein R⁶⁰ is H, alkyl, alkanoyl, alkenoyl, aryl, arylalkyl,alkenyl, alkynyl, or, alkyl, aryl, arylalkyl, alkenyl, alkynylsubstituted by halo, OH, SH, CF₃,alkanoylthienyl, or alkanoyloxy;

[0097] wherein R⁶¹ is H, alkyl, aryl, arylalkyl, alkenyl, or alkynyl;

[0098] and d is 0, 1 or 2; or a pharmaceutically acceptable saltthereof.

[0099] In a preferred embodiment, R^(30′) and R^(20″) in the compoundsof Formula IV are each H.

[0100] The present invention provides a compound represented by theformula V

[0101] wherein R²⁰CO— is a natural or unnatural amino acid moietyrepresented by the formulas

[0102] Y=H, CH₃; CH₃CH₂—; CH₃CH₂CH₂—; Me₂CH—; Me₂CH₂CH₂—;CH₃CH₂CH(Me)—PhCH₂—; HOOCCH₂CH₂—; HSCH₂—; HOOCCH₂—; MeSCH₂CH₂—; HOCH₂—;

[0103] or Y is H₂N(CH₂)₄— or CH₃CH(OH)—; or a pharmaceuticallyacceptable salt thereof;

[0104] or Y taken together with the α carbon and N form

[0105] or a phamaceutically acceptable salt thereof;

[0106] or Y taken together with the a carbon and N form

[0107] or a phamaceutically acceptable salt thereof.

[0108] The present invention provides a compound represented by theformula VI:

[0109] or a pharmaceutically acceptable salt thereof;

[0110] wherein AA is a natural or unnatural amino acid moiety of theformula:

[0111] The present invention also provides a compound represented byformula VII

[0112] wherein R⁵⁰ is CH₃CH(NH₂)—CO—, CH₃CH₂(CH₃)CHCH(NH₂)—CO— orH₂N(CH₂)₄CH(NH₂)—CO—;

[0113] or a pharmaceutically acceptable salt thereof.

[0114] The present invention also provides pharmaceutical compositionsfor treating susceptible viral infections comprising a compound offormula VII and at least one pharmaceutically acceptable carrier.

[0115] The present invention also provides a method of treating apatient with a susceptible viral infection which comprises administeringto said patient an effective amount of a compound of formula VII .

[0116] The present invention also provides a method of treating apatient infected with chronic hepatitis C which comprises administeringto said patient an effective amount of a compound of formula VII inassociation with an effective amount of an interferon alfa for a timesufficient to eradicate detectable HCV-RNA levels, wherein the compoundrepresented by the formula VII:

[0117] wherein R⁵⁰ is CH₃CH(NH₂)—CO—, CH₃CH₂(CH₃)CHCH(NH₂)—CO— orH₂N(CH₂)₄CH(NH₂)—CO—

[0118] or a pharmaceutically acceptable salt thereof

[0119] The present invention provides a compound represented by theformula VIII

[0120] or a pharmaceutically acceptable salt thereof.

[0121] The present invention also provides a method of treating apatient infected with chronic hepatitis C which comprises administeringto said patient an effective amount of a compound of formula VIII

[0122] or a pharmaceutically acceptable salt thereof, in associationwith an effective amount of an interferon alfa for a time sufficient toeradicate detectable HCV-RNA levels.

DETAILED DESCRIPTION

[0123] The term “alkyl” as used herein means straight and branchedcarbon chains of one to twenty carbons, preferably one to six carbonsand more preferably one to three carbons.

[0124] The term “alkenyl” as used herein means straight and branchedchain alkyl groups containing at least one carbon-carbon double bond andtwo to twenty carbons, preferably two to eight carbons.

[0125] The term “alkynyl” as used herein means straight and branchedchain alkyl groups containing at least one carbon-carbon triple bond andtwo to twenty carbons, and preferably two to six carbons containing atleast one carbon-carbon triple bond.

[0126] The term “cycloalkyl” as used herein means carbocyclic rings ofthree to twelve carbons, preferably three to seven carbons, and morepreferably three to six carbons optionally substituted by one doublebond.

[0127] The term “alkanoyl” as used herein means straight and branchedchain alkanoyl groups of one to twenty carbons, preferably two totwelve, more preferably two to ten and most preferably two to sixcarbons.

[0128] The term “alkenoyl” as used herein means straight and branchedchain alkenoyl groups of one to twenty carbons containing at least onecarbon-carbon double bond, preferably two to twelve, or more preferablytwo to ten and most preferably two to six carbons containing at leastone carbon-carbon double bond.

[0129] The term “halo” as used herein means fluroro, chloro or bromo,preferably fluroro or chloro.

[0130] The term “alkynoyl” as used herein means straight and branchedchain alkenoyl groups of one to twenty carbons containing at least onecarbon-carbon triple bond, preferably two to twelve, or more preferablytwo to ten and most preferably two to six carbons containing at leastone carbon-carbon triple bond.

[0131] The term “alkoxy” as used herein means straight and branchedchain alkyl groups containing one bond to oxygen at the one carbon andone to ten carbons. Typically suitable alkoxy includes methoxy, ethoxyand tert-butoxy.

[0132] The term “aryl” as used herein (including the aryl portion ofaryloxy and aralkyl, e.g., benzyl)-represents a carbocyclic groupcontaining from 6 to 15 carbon atoms and having at least one aromaticring (e.g., aryl is a phenyl ring), or is a polycyclic aromaticcontaining one or more heteroatoms, e.g., N or S such as quinoyl,isoquinolyl with all available substitutable carbon atoms of thecarbocyclic group being optionally substituted (e.g., 1 to 3) with oneor more of halogen, alkyl, or alkyl substituted by OH, halo, aminodiaklylamino, alkanoylamino, or is alkanoyl hydroxy, alkoxy, CN,phenoxy, CF₃, amino, alkylamino, dialkylamino, SH, S⁻M⁺ or —NO₂; and theterm “M⁺” represents an alkali metal cation such as Na⁺, K⁺ and Li⁺.

[0133] The term “arylalkyl” as used herein means an alkyl groupsubstituted by an aryl group.

[0134] The term “heterocyclic” as used herein means a cyclic grouprepresented by the formula;

[0135] wherein J is —CHR⁶⁰—, —O—, —NR⁶⁰—, —S—, —SO— or —SO₂—.,and I is—CR⁶⁰ or —N—; and R⁶⁰ is H, alkyl or aryl., and g and g′ areindependently 1 to 4 and g+g′ are 2, 3, 4 or 5. Typically suitableheterocyclics include

[0136] The term “halo” as used herein means fluoro, chloro, bromo oriodo,. preferably fluroro or chloro.

[0137] In a preferred embodiment of the present invention, the compoundsof formula I have one or two of R², R³ and R⁵ equal to R⁶ (W)_(x)CO—,(HO)₂PO— or R⁶(W)_(x)PO(OH)— and at least one of R², R³ and R⁵ equal toH. Most preferred compounds of formula I have R²═R³═H and R⁵ equal toR⁶(W)_(x)CO—, (HO)₂PO— or R⁶(W)_(x)PO(OH)—. In the preferred embodimentsof R⁶-(W)_(x)CO— and R⁶(W)_(x)-PO(OH)—, W=O and x=0 or 1. In thepreferred embodiments of R⁶-(W)_(x)CO— and R⁶(W)_(x)P(OH)O— includeR¹⁷(CH₂)_(m)—NR^(7b)R^(7a)—(CH₂)_(n)OCO— andR¹⁷(CH₂)_(m)—NR^(7b)R^(7a)—(CH₂)_(n)—O—PO(OH), wherein m=0 to 4 and n=0to 4; and R¹⁷ is H, Me, MeCO— or Me₂N—

[0138] and R^(7a)R^(7b)N (CH₂)_(f)—(CHR^(7a))_(e)OCO— or R^(7a)R^(7b)N(CH₂)_(f)—(CHR^(7a))_(e)CO—

[0139] wherein f=0 to 4 and e=1 to 5, and R^(7a)R^(7b)N is Me₂N—, MeHN—or MeCONH—. In most preferred embodiments of R⁶(W)_(x)CO—, x=0 and R⁶COis one of

[0140] wherein X is independently OH, alkanoyl, e.g.,COCH₃, NH₂,alkanoylamino, e.g., NHCOCH₃, hydroxyalkyl, e.g., CH₂OH, alkoxy, e.g.,OCH₃ NO₂, or halo, e.g., F, Br or Cl.

[0141] Preferably R⁶CO is

[0142] wherein X is NO₂, NH₂, NHCOCH₃ or OCH₃.

[0143] More preferably R⁶CO is

[0144] or R⁶ in R⁶CO is one of HOCH(CH₃)CO—, HOCH(C₆H₅)CO—,C₂H₅CH(OH)CO— or CH₃CO₂(CH₂)₂CO—or R⁶CO is a natural or unnaturala-amino acid residue—

[0145] wherein Y=H, CH₃; CH₃CH₂—; CH₃CH₂CH₂—; Me₂CH—; Me₂CH₂CH₂—;CH₃CH₂CH(Me)—PhCH₂—; HOOCCH₂CH₂—; HSCH₂—; HOOCCH₂—; MeSCH₂CH₂—; HOCH₂—;CH₂—;

[0146] or Y is H₂N(CH₂)₄— or CH₃CH(OH)—; or a pharmaceuticallyacceptable salt thereof;

[0147] or Y taken together with the a carbon and N form

[0148] or a pharmaceutically acceptable salt thereof.

[0149] or

[0150] wherein R²¹ is as defined hereinabove; or a pharmaceuticallyacceptable salt thereof.

[0151] Other preferred embodiments for R⁶CO in the compounds of formulaI include

[0152] (CH₃)₃CO—, C₆H, CO—,(HO)₂PO— and

[0153] L-C₆H₂CH₂OCONHCH(CH₃)CO—, i.e., C₆H₅CH₂OCONHCH

[0154] In a preferred embodiment of the present invention, the compoundsof formula II have one or two of R ², R³ and R⁵ equal to R²⁰(W)_(x)CO—or R²⁰(W)_(x)PO(OH)— and at least one of R², R³ and R⁵ equal to H. Mostpreferred compounds of formula II have R²═R³═H and R⁵ equal toR20⁶(W)_(x)CO— or R²⁰(W)_(x)P(OH)O—. In the preferred embodiments ofR²⁰(W)_(x)CO— and R²⁰(W)_(x)P(OH)O—, W=O and x=0 or 1. In the preferredembodiments of R²⁰(W)_(x)CO— and R²⁰(W)_(x)P(OH)O— includeR²⁷(CH₂)_(m)—NR²¹R²¹R²²—(CH₂)_(n)OCO— andR²⁷(CH₂)_(m)—NR²¹R²²—(CH₂)_(n)CO—, R²⁷(CH₂)_(m)—NR²¹R²²—(CH₂)_(n)OPO(OH)— wherein m=0 to 4 and n=1 to 5; R²⁷ is H, Me, MeCO— or Me₂N—, R²¹is H, Me, or MeCO—R²² is H, Me, or MeCH₂and R²¹R²² N is Me₂N—, MeHN— orMeCONH—.

[0155] In most preferred embodiments of R²⁰(W)_(x)CO—, x=0 and R²⁰CO isHOCH(CH₃)CO—, HOCH(C₆H₅)CO—, C₂H₅CH(OH)CO— or CH₃CO₂(CH₂)₂CO— or R²⁰COis a natural α-amino acid residue

[0156] Y=H, CH₃; CH₃CH₂—; CH₃CH₂CH₂—; Me₂CH—; Me₂CH₂CH₂—;CH₃CH₂CH(Me)—PhCH₂—; HOOCCH₂CH₂—; HSCH₂—; HOOCCH₂—; MeSCH₂CH₂—; HOCH₂—;CH₂—;

[0157] or Y is H₂N(CH₂)₄— or CH₃CH(OH)—;

[0158] or Y taken together with the a carbon and N form

[0159] wherein R²¹ is as defined hereinabove; or a pharmaceuticallyacceptable salt thereof.

[0160] or R²⁰CO is

[0161] *(and substituted Ph)

[0162] or a pharmaceutically acceptable salt thereof;

[0163] wherein Ph is phenyl and phenyl substituted by halo, CN, NO₂, OH,CO₂H, or alkoxy.

[0164] The compounds of formulas I to VIII metabolize in vivo intoribavirin and are useful for treating susceptible viral infectionstreatable with ribavirin, alone, or in combination with other ant-viraltherapies eg., interferon-alfa, and so-called Highly ActiveAntiretroviral Therapy (“HAART”). A -M. Vandamme et al., AntiviralChemistry & Chemotherapy, 9:187-203 (1998) disclose current clinicaltreatments of HIV-1 infections in man including at least triple drugcombinations or so-called Highly Active Antiretroviral Therapy(“HAART”); HAART involves various combinations of nucleoside reversetranscriptase inhibitors (“NRTI”), non-nucleoside reverse transcriptaseinhibitors (“NNRTI”) and HIV protease inhibitors (“Pi”). The treating ofpatients having chronic hepatitis C with the compounds of formulasl-VIII is performed as part of a combination therapy withinterferon-alfa, including interferon alfa-2a, interferon alfa-2b,consensus interferon especially interferon alfa-2b as well as pegylatyedinterferon alfa-2a and pegylatyed interferon alfa-2b.

[0165] The present invention provides methods and pharmaceuticalcompositions containing a compound of formulas II-VIII for treatingsusceptible viral infections, especially hepatitis C viral infections.

[0166] The term “susceptible viral infections” as used herein meansviral infections caused by a wide range of RNA and DNA viruses,including, but not limited to, the families of viruses such asflaviruses-including the genus flavirus, pestivirus of which Kunjinvirus is a member, and hepavirus of which hepatitis C virus is a member,and arbovirus of which the West Nile virus is a member-orthomyxoviruses,paramyxoviruses, arenaviruses, bunyaviruses, herpes viruses,adenoviruses, poxviruses, and retroviruses.

[0167] Typical suitable “susceptible viral infections” include influenzaA and B viral infections; parainfluenza viral infections, respiratorysyncytial virus(“RSV”) infections such as RSV bronchiolitis and RSVpneumonia especially such RSV infections in children and infants as wellas RSV pneumonia in patients with preexisting cardiopulmonary disease,measles viral infections, Lassa fever viral infections, KoreanHaemorrhagic fever infections, hepatitis B viral (HBV) infections,CrimeanCongo-Haemorrhagic and HCV infections and HIV-1 infections,encephalitis infections such as caused by West Nile virus or Kunjinvirus or the St. Louis encephalitis infections as well as viralinfections found in immunocompromised patients. Other susceptible viralinfections are disclosed in U.S. Pat. No. 4,211,771 at column 2, line 21to column 3 line 37; doses and dose regimens and formulations aredisclosed at column 3, line 4 to column 9, line 5; see also CanadianPatent No. 1,261,265. Sidwell, R. W., et al. Pharmacol. Ther., 1979, Vol6 pp 123-146 discloses that the in vivo antiviral experiments conductedwith ribavirin generally confirm one broad-spectrum antiviral activityseen in vitro and states that the efficacy of ribavirin is quitedependent upon the site of infection; the manner of treatment; the ageof the animal and the virus dosage utilized. Tables 4 and 5 on page 127list the RNA and DNA virus infections significantly inhibited in vivo byribavirin.

[0168] The in vitro inhibitory concentrations of ribavirin are disclosedin Goodman & Gilman's “The Pharmacological Basis of Therapeutics”, NinthEdition, (1996) McGraw Hill, N.Y., at pages 1214-1215. The Virazoleproduct information discloses a dose of 20 mg/mL of Virazole aerosol for18 hours exposure in the 1999 Physicians Desk Reference at pages1382-1384.

[0169] Ribavirin dosage and dosage regimens are also disclosed bySidwell, R. W., et al. Pharmacol. Ther 1979 Vol 6. pp123-146 in section2.2 pp 126-130. Fernandes, H., et al., Eur. J. Epidemiol., 1986, Vol2(1) pp 1-14 at pages 4-9 disclose dosage and dosage regimens for oral,parenteral and aerosol administration of ribavirin in variouspreclinical and clinical studies.

[0170] The term “patients having hepatitis C infections” as used hereinmeans any patient-including a pediatric patient having hepatitis C andincludes treatment-naive patients having hepatitis C infections andtreatment-experienced patients having hepatitis C infections as well asthose pediatric, treatment-naive and treatment-experienced patientshaving chronic hepatitis C infections.

[0171] These patients having hepatitis C include those who are infectedwith multiple HCV genotypes including type 1 as well as those infectedwith, e.g., HCV genotypes 2, 3, 4, 5 and/or 6 and other possible HCVgenotypes.

[0172] The term “treatment-naive patients having hepatitis C infections”as used herein means patients with hepatitis C who have never beentreated with ribavirin or any interferon, including but not limited tointerferon-alfa, or pegylated interferon alfa.

[0173] The term “treatment-experienced patients having hepatitis Cinfections” as used herein means patients with hepatitis C who have beentreated with ribavirin or any interferon, including but not limited tointerferon-alfa, or pegylated interferon alfa, including relapsers andnon-responder.

[0174] The term “relapsers” as used herein means treatment-experiencedpatients with hepatitis C who have relapsed after initial response toprevious treatment with interferon alone, or in combination withribavirin.

[0175] The term “non-responders” as used herein meanstreatment-experienced patients with hepatitis C who have not respondedto prior treatment with any interferon alone, or in combination withribavirin.

[0176] When the pegylated interferon-alfa administered is a pegylatedinterferon alfa-2b, the therapeutically effective amount of pegylatedinterferon alfa-2b administered during the treatment in accordance withthe present invention, including in first and second treatment timeperiods, is in the range of about 0.1 to 9.0 micrograms per kilogram ofpegylated interferon alfa-2b administered per week, in single or divideddoses, preferably once a week (QW) or twice a week(BIW), preferably inthe range of about 0.1 to about 9.0 micrograms per kilogram of pegylatedinterferon alfa-2b administered once a week (QW) or in the range ofabout 0.05 to about 4.5 micrograms per kilogram of pegylated interferonalfa-2b administered twice a week(BIW), or is in the range of about 0.5to about 3.0 micrograms per kilogram of pegylated interferon alfa-2badministered per week, preferably in the range of about 0.5 to about 3.0micrograms per kilogram of pegylated interferon alfa-2b administeredonce a week (QW) or in the range of about 0.25 to about 1.5 microgramsper kilogram of pegylated interferon alfa-2b administered twice a week ,or is in the range of about 0.75 to about 1.5 micrograms per kilogram ofpegylated interferon alfa-2b administered per week, most preferably isin the range of about 0.75 to about 1.5 micrograms per kilogram ofpegylated interferon alfa-2b administered once a week or about 0.375 toabout 0.75 micrograms per kilogram of pegylated interferon alfa-2badministered twice a week.

[0177] When the pegylated interferon-alfa administered to pediatricpatients is a pegylated interferon alfa-2b, the therapeuticallyeffective amount of pegylated interferon alfa-2b administered during thetreatment in accordance with the present invention is in the range ofabout 0.1 to 9.0 micrograms per kilogram of pegylated interferon alfa-2badministered per week, in single or divided doses, preferably once aweek (QW) or twice a week(BIW), more preferably about 0.1 to about 9.0micrograms per kilogram of pegylated interferon alfa-2b administeredonce a week (QW), or about 0.05 to about 4.5 micrograms per kilogram ofpegylated interferon alfa-2b administered per week, in single or divideddoses, preferably once a week (QW) or twice a week(BIW), more preferablyabout 0.05 to about 4.5 micrograms per kilogram of pegylated interferonalfa-2b administered once a week, or preferably about 0.75 to about 3.0micrograms per kilogram of pegylated interferon alfa-2b administered insingle or divided doses, preferably once a week (QW) or twice aweek(BIW), more preferably about 0.75 to about 3.0 micrograms perkilogram of pegylated interferon alfa-2b administered once a week orabout 0.375 to about 1.5 micrograms per kilogram of pegylated interferonalfa-2b administered twice a week, and most preferably about 2.25 toabout 2.6 micrograms per kilogram of pegylated interferon alfa-2badministered once a week or about 1.1 to about 1.3 micrograms perkilogram of pegylated interferon alfa-2b administered twice a week(BIW).

[0178] When the pegylated interferon-alfa administered is a pegylatedinterferon alfa-2a, the therapeutically effective amount of pegylatedinterferon alfa-2a administered in accordance with the presentinvention, is in the range of about 50 micrograms to about 500micrograms once a week(“QW”). preferably about 150 micrograms to about250 micrograms QW or the effective amount is in the range of about 50micrograms to about 250 micrograms twice a week, preferably about 100micrograms to about 125 micrograms twice a week.

[0179] When the pegylated interferon-alfa administered to a pediatricpatient is a pegylated interferon alfa-2a, the therapeutically effectiveamount of pegylated interferon alfa-2a administered in accordance withthe present invention, is in the range of about 50 micrograms to about500 micrograms once a week(“QW”), preferably about 300 micrograms toabout 375 micrograms QW or the therapeutically effective amount ofpegylated interferon alfa-2a administered to a pediatric patient is inthe range of about 50 micrograms to about 250 micrograms twice a week,preferably about 150 micrograms to about 190 micrograms once a week

[0180] The esters of ribavirin represented by formulas I-VIII areadministered to the patient having chronic HCV in association withpegylated interferon-alfa, that is, before, after or concurrently withthe administration of the pegylated interferon alfa. The pegylatedinterferon-alfa dose is preferably administered during the same periodof time that the patient receives doses of esters of ribavirinrepresented by formulas I-VIII . The amount of esters of ribavirinrepresented by formulas I-VIII administered concurrently with thepegylated interferon-alfa is from about 200 to about 1600 mg per day,preferrably about 300 to about 1200 mg/day or about 400 to about 800 mgday and most preferably about 400 to about 600 mg a day. The pegylatedinterferon-alfa dose is also preferably administered to the pediatricpatient during the same period of time that such patient receives dosesof the esters of ribavirin represented by formulas l-VIII . The amountof the 5′-amino acid esters of ribavirin represented by formulasIII-VIII administered to the pediatric patient having chronic HCVconcurrently with the interferon-alfa is from about 1 to about 30 mg perkilogram per day, preferably from about 4 to about 15 mg per kilogramper day, more preferably about 6, 8 or 15 mg per kilogram per day, mostpreferably about 8 to 10 mg per kilogram per day in divided doses.

[0181] Pegylated interferon-alfa formulations are not effective whenadministered orally, so the preferred method of administering thepegylated interferon-alfa is parenterally, preferably bysub-cutaneous(SC), intravenous(IV), or intramuscular(IM) injection. The5′-amino acid esters of ribavirin represented by formula I may beadministered orally in capsule, tablet , or liquid form, intranasally asan aerosol by nasal spray or parenterally, preferably by SC, IV, or IMinjection. The esters of ribavirin represented by formulas I-VIII may beorally administered in association with the parenteral administration ofpegylated interferon-alfa . Of course, other types of administration ofboth medicaments, as they become available, are contemplated, such astransdermally, by suppository, by sustained release dosage form, and bypulmonary inhalation. Any form of administration will work so long asthe proper dosages are delivered without destroying the activeingredient

[0182] The term “interferon-alfa ” as used herein means the family ofhighly homologous species-specific proteins that inhibit viralreplication and cellular proliferation and modulate immune response.Typical suitable interferon-alfas include, but are not limited to,recombinant interferon alfa-2b, such as Intron-A interferon availablefrom Schering Corporation, Kenilworth, N.J., recombinant interferonalfa-2a, such as Roferon interferon available from Hoffmann-La Roche,Nutley, N.J., recombinant interferon alpha-2c, such as Berofor alpha 2interferon available from Boehringer Ingelheim Pharmaceutical, Inc.,Ridgefield, Conn., interferon alpha-n1, a purified blend of natural alfainterferons, such as Sumiferon available from Sumitomo, Japan or asWellferon interferon alpha-n1 (INS) available from the Glaxo-WellcomeLtd., London, Great Britain, or a consensus alpha interferon, such asthose described in U.S. Pat. Nos. 4,897,471 and 4,695,623 (especiallyExamples 7, 8 or 9 thereof) and the specific product available fromAmgen, Inc., Newbury Park, Calif., or interferon alfa-n3 a mixture ofnatural alfa interferons made by Interferon Sciences and available fromthe Purdue Frederick Co., Norwalk, Conn., under the Alferon Tradename.The use of interferon alfa-2a or alpha 2b is preferred. Since interferonalpha 2b, among all interferons, has the broadest approval throughoutthe world for treating chronic hepatitis C infection, it is mostpreferred. The manufacture of interferon alpha 2b is described in U.S.Pat. No. 4,530,901.

[0183] The term “pegylated interferon alfa” as used herein meanspolyethylene glycol modified conjugates of interferon alfa, preferablyinterferon alfa-2a and -2b. The preferred polyethylene-glycol-interferonalfa -2b conjugate is PEG₁₂₀₀₀-interferon alfa 2b. The phrases “12,000molecular weight polyethylene glycol conjugated interferon alpha” and“PEG₁₂₀₀₀-IFN alfa” as used herein mean conjugates such as are preparedaccording to the methods of International Application No. WO 95/13090and containing urethane linkages between the interferon alfa-2a or -2bamino groups and polyethylene glycol having an average molecular weightof 12000.

[0184] The preferred PEG₁₂₀₀₀-interferon alfa-2b is prepared byattaching a PEG polymer to the epsilon amino group of a lysine residuein the IFN alfa-2b molecule. A single PEG₁₂₀₀₀ molecule is conjugated tofree amino groups on an IFN alfa-2b molecule via a urethane linkage.This conjugate is characterized by the molecular weight of PEG₁₂₀₀₀attached. The PEG12000-IFN alfa-2b conjugate is formulated as aIyophilized powder for injection. The objective of conjugation of IFNalfa with PEG is to improve the delivery of the protein by significantlyprolonging its plasma half-life, and thereby provide protracted activityof IFN alfa.

[0185] Other pegylated interferon alfa conjugates can be prepared bycoupling an interferon alfa to a water-soluble polymer. A non-limitinglist of such polymers include other polyalkylene oxide homopolymers suchas polypropylene glycols, polyoxyethylenated polyols, copolymers thereofand block copolymers thereof. As an alternative to polyalkyleneoxide-based polymers, effectively non-antigenic materials such asdextran, polyvinylpyrrolidones, polyacrylamides, polyvinyl alcohols,carbohydrate-based polymers and the like can be used. Such interferonalfa-polymer conjugates are described in U.S. Pat. No. 4,766,106, U.S.Pat. No. 4,917,888, European Patent Application No. 0 236 987, EuropeanPatent Application Nos. 0510 356, 0 593 868 and 0 809 996 (pegylatedinterferon alfa-2a) and International Publication No. WO 95/13090.

[0186] Pharmaceutical composition of pegylated interferon alfa suitablefor parenteral administration may be formulated with a suitable buffer,e.g., Tris-HCl, acetate or phosphate such as dibasic sodiumphosphate/monobasic sodium phosphate buffer, and pharmaceuticallyacceptable excipients, e.g., sucrose, carriers, e.g., humanorrecombinant plasma albumin, tonicity agents, e.g. NaCl, preservatives,e.g., thimerosol, cresol or benyl alcohol, and surfactants, e.g., tweensor polysorabates in sterile water for injection. The pegylatedinterferon alfa-may be stored as lyophilized powders under arefrigeration at 2°-8° C. The reconstituted aqueous solutions are stablewhen stored between 2° and 8° C. and used within 24 hours ofreconstitution. See for example U.S. Pat. Nos., 4,492,537; 5,762,923 and5,766,582.The reconstituted aqueous solutions may also be stored inprefilled, multi-dose syringes such as those useful for delivery ofdrugs such as insulin. Typical suitable syringes include systemscomprising a prefilled vial attached to a pen-type syringe such as theNOVOLET Novo Pen available from Novo Nordisk, as well as prefilled,pen-type syringes which allow easy self-injection by the user. Othersyringe systems include a pen-type syringe comprising a glass cartridgecontaining a diluent and lyophilized pegylated interferon alfa powder ina separate compartment.

[0187] A person suffering from chronic hepatitis C infection may exhibitone or more of the following signs or symptoms:

[0188] (a) elevated ALT,

[0189] (b) positive test for anti-HCV antibodies,

[0190] (c) presence of HCV as demonstrated by a positive test for thepresence of HCV-RNA in the serum,

[0191] (d) clinical stigmata of chronic liver disease,

[0192] (e) hepatocelluar damage.

[0193] The combination therapy of pegylated interferon-alfa and theesters of ribavirin represented by formulas l-VIII and preferably the5′-amino acid esters of ribavirin represented by formulas III-VIII mayalso be administered in association with anti-retroviral therapy, e.g.,HAART, to the patient co-infected with the HIV-1 and HCV infection andexhibiting one or more of the above signs or symptoms in amountssufficient to eliminate or at least alleviate one or more of the signsor symptoms of hte HCV infection , and to lower the HIV-1-RNA andHCV-RNA serum levels each by at least a power of ten, and preferably toeradicate detectable HCV-RNA at least by the end of about 20 to about 50weeks, preferably at least 24 weeks to 48 weeks and to maintain nodetectable HCV-RNA for at least 24 weeks after the end of the about 20to about 50 weeks. Administration of the 5′-amino acid esters ofribavirin represented by formula I may be discontinued after the end ofthe second time period depending upon the judgment of the attendingclinician.

[0194] The term “no detectable HCV-RNA” in the context of the presentinvention means that there are fewer than 100 copies of HCV-RNA per mlof serum of the patient as measured by quantitative, multi-cycle reversetranscriptase PCR methodology. HCV-RNA is preferably measured in thepresent invention by research-based RT-PCR methodology well known to theskilled clinician. This methodology is referred to herein asHCV-RNA/qPCR. The lower limit of detection of HCV-RNA is 100 copies/mL.Serum HCV-RNA/qPCR testing and HCV genotype testing will be performed bya central laboratory. See also J. G. McHutchinson et al. (N. Engl. J.Med., 1998, 339:1485-1492), and G. L. Davis et al. (N. Engl. J. Med.339:1493-1499).

Biological Activity

[0195] The compounds of formulas I-VIII are useful for treating patientshaving susceptible viral infections such as chronic hepatitis C as partof a Combination Therapy with interferon-alfa, especially interferonalfa-2b. The compounds of formulas I and II wherein R⁵ isR⁶(W)_(x)C)—,R⁶(W)_(x)CS, (HO)₂PO—, R⁶(W)_(x)P(OH)O— or HOSO₂ ⁻metabolizes in vivo into ribavirin.

[0196] Compounds of formula I wherein R²═R³═H and R⁵═(HO)₂PO—,or

[0197] or (CH₃)₃CO—, or C₆H₅CO— or C₆H₅—CH₂OC(O)NH

[0198] have produced higher plasma concentration of ribavirin afteradministration to rats. TABLE 1 Ribavirin Concentrations of pooled Rat¹Plasma (2 rats/pool) following oral administration of 40 mpk of thecompounds of formula I in 20% hydroxypropyl-beta-cyclodextrin AUC(pooled)³ C.V.⁴ Conc. (6 hr) C.V.⁴ Compound² (ng ·hr/mL (%) (ng/mL) (%)A 1523.65 23.56 142.54 49.37 B 1309.76 1.68 241.83 19.61 C 1303.34 67.42170.42 37.78 D 1065.88 29.12 116.33 10.73 E 754.77 74.42 122.71 44.68

[0199] For preparing pharmaceutical compositions from the compoundsdescribed by this invention, inert, pharmaceutically acceptable carrierscan be either solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18th Edition, (1990), Mack Publishing Co., Easton, Pa.

[0200] Liquid form preparations include solutions, suspensions andemulsions. As an example may be mentioned water or water-propyleneglycol solutions for parenteral injection or addition of sweeteners andopacifiers for oral solutions, suspensions and emulsions. Liquid formpreparations may also include solutions for intranasal administration.

[0201] Aerosol preparations suitable for inhalation may includesolutions and solids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

[0202] Also included are solid form preparations which are intended tobe converted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

[0203] The compounds of the invention may also be deliverabletransdermally. The transdermal compositions can take the form of creams,lotions, aerosols and/or emulsions and can be included in a transdermalpatch of the matrix or reservoir type as are conventional in the art forthis purpose.

[0204] Preferably the compound is administered orally.

[0205] Preferably, the pharmaceutical preparation is in a unit dosageform. In such form, the preparation is subdivided into suitably sizedunit doses containing appropriate quantities of the active component,e.g., an effective amount to achieve the desired purpose.

[0206] The quantity of active compound in a unit dose of preparation maybe varied or adjusted from about 0.01 mg to about 1000 mg, preferablyfrom about 0.01 mg to about 750 mg, more preferably from about 0.01 mgto about 500 mg, and most preferably from about 0.01 mg to about 250 mg,according to the particular compound and particular application.

[0207] The actual dosage employed may be varied depending upon therequirements of the patient and the severity of the condition beingtreated. Determination of the proper dosage regimen for a particularsituation is within the skill of the art. For convenience, the totaldaily dosage may be divided and administered in portions during the dayas required.

[0208] The amount and frequency of administration of the compounds ofthe invention and/or the pharmaceutically acceptable salts thereof willbe regulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/kg/day to about 100 mg/kg/day, in two to four divided doses.

[0209] In a preferred embodiment of the present invention, thosepatients co-infected with HIV-1 and HCV infections are treated withpegylated interferon alfa in combination with the preferred 5′-aminoacid esters of ribavirin represented by formulas III to VIII and a HAARTcombination considered appropriate by the attending clinician and thepatient.. See also J. G. McHutchinson et al. (N. Engl. J. Med., 1998,339:1485-1492), and G. L. Davis et al. (N. Engl. J. Med. 1998,339:1493-1499).

[0210] The preferred compounds of formulas III-VIII are useful fortreating patients having susceptible viral infections, e.g., chronichepatitis C. The compounds of formulas III-VIII metabolize in vivo intoribavirin and are useful for treating susceptible viral infectionstreatable with ribavirin, alone, or in combination with other anti-viraltherapies, e.g., interferon-alfa and HAART. The treating of patientshaving chronic hepatitis C with the compounds of formulas III-VIII isperformed as part of a combination therapy with interferon-alfa,especially interferon alfa-2b.

[0211] Compounds of formulas III VIII metabolize in vivo into ribavirinand have produced higher plasma concentrations of ribavirin after oraladministration of a compound of formula VII to rats and monkeys comparedto administration of ribavirin. The pharmacokinetics of the preferredcompounds of formulas VII are presented in Tables 2 & 3 TABLE 2Ribavirin Concentrations of Pooled Rat¹ Plasma (2 rats/pool) FollowingOral Administration of 20 mpk Ribavirin Equivalent Amounts of Salts ofthe Compounds of Formula VII in 20%Hydroxypropyl-beta-cyclodextrin(HPBCD) AUC (pooled)³ C.V.⁴ Conc. (6 hr)C.V.⁴ Compound² (ng.hr/mL) (%) (ng/mL) (%) A 1238 81.4 152 30.5 B 255425.0 226 20.0 C 1011 *** 294 — D 2043 1.4 173 67.3 ¹Male Sprague Dawely(CD) rats (N = 2)obtained from Charles River, Wilmington, MA01887:Single dose,PO, (Fasted overnight); 20 mg/Kg(mpk) ribavirinequivalent PO dose of the compound of formula I in 20% HPBCD(w/v);Concentration: 4 mg/ml ribavirin equivalent and dosing volume :5 ml/Kg.²(a) Compound A is the compound of formula VII wherein R⁵⁰ is H, i.e. ,ribavirin (b) Compound B is the trifluoroacetate salt of the compound offormula VII wherein R⁵⁰is [CF₃CO₂ ⁻] L—CH₃CH₂(CH₃)CHCH(NH₃ ^(⊕))—CO—.(c) Compound C is the ditosylate salt of the compound of formula VIIwherein R⁵⁰is 2[p-CH₃C₆H₄SO₃ ^(−]) L—H₃N^(⊕)(CH₂)₄CH(NH₃⊕)—CO—. (d)Compound D is the tosylate salt of the compound of formula VII whereinR⁵⁰is [p-CH₃C₆H₄SO₃ ^(−] L—CH) ₃CH(NH₃ ^(⊕))—CO—, i.e.,

³Area under the curve measured from 0 to 6 hrs. after oraladministration to 2 rats of an aqueous solution of compounds of formulaVII in 20% HPBCD. ⁴% CV is percent coefficient of variation which is arelative measure of variability. See Steele and Torrie, “Principles andProcedures of Statistics”, (1980) 2nd Edition, McGraw-Hill, NY, at page27.

[0212] TABLE 3 Ribavirin Concentrations of Pooled Cynomolgus Monkeys¹Plasma (2 monkeys/pool) Following Oral Administration of 10 mpk ofRibavirin Equivalent Amounts of Salts of Compounds of Formula VIIDissolved in 0.4% Methylcellulose(MC) AUC (24)³ AUC(48 hr). AUC(72 hr)Cmax. Compound² (ng.hr/mL) (ng.hr/mL) (ng.hr/mL) (ng/mL) A 4013 55065902 398⁴ B 4791 5749 5749 831⁵ C 6033 8050 8381 661⁶ D 9072 11632 125281012⁷ Non-naive male Cynomolgus monkeys(N = 2) ²(a) Compound A is thecompound of formula VII wherein R is H, i.e. , ribavirin. (b) Compound Bis the trifluoroacetate salt of the compound of formula VII wherein R⁵⁰is [CF₃CO₂ ⁻] L—CH₃CH₂(CH₃)CHCH(NH₃ ^(⊕))—CO—. (c) Compound C is theditosylate salt of the compound of formula VII wherein R⁵⁰ is2[p-CH₃C₆H₄SO₃ ^(−] L—H) ₃N^(⊕)(CH₂)₄CH(NH₃ ^(⊕))—CO— (d) Compound D isthe tosylate salt of the compound of formula VI wherein R⁵⁰ is[p-CH₃C₆H₄SO₃ ⁻] L—CH₃CH(NH₃ ^(⊕))—CO—, i.e.,

³Area under the curve measured from 0 to 24, 48 or 72 hrs. after oraladministration to non-naive male Cynomolgus monkeys of an oral gavage ofa 0.4% MC solutions of the compounds of formula I at a target dose of 10mg (free base)/Kg and at a target dose volume of 2 ml/Kg.. ⁴Tmax for Ais 1.5 hrs. 5 Tmax for B is 1.0 hrs. 6 Tmax for C is 1.5 hrs. 7 Tmax forD is 1.5 hrs

[0213] The pharmaceutical compositions of the preferred 5′-amino acidesters of ribavirin of the present invention (represented by formulasIII-VIII) may be adapted for any mode of administration e.g., for oral,parenteral, e.g., subcutaneous (“SC”), intramuscular (“IM”), intravenous(“IV”) and intraperitoneal (“IP”), topical or vaginal administration orby inhalation (orally or intranasally). Preferably the ribavirincompounds represented by formula I are administered orally.

[0214] Such compositions may be formulated by combining a compound offormulas III-VIII or an equivalent amount of a pharmaceuticallyacceptable salt of compound I with an suitable, inert, pharmaceuticallyacceptable carrier or diluent which may be either solid or liquid. Thecompounds of formulas III-VIII are preferably converted into thepharmaceutically acceptable acid addition salts by adding to compoundsof formulas III-VIII an equivalent amount (or two equivalents in thecase of for example the lysine ester) of a pharmaceutically acceptableacid. Typically suitable pharmaceutically acceptable acids include themineral acids, e.g.,HNO₃ H₂SO₄, H₃PO₄,HCl, HBr, organic acids,including, but not limited to, acetic, trifluoroacetic, propionic,lactic, maleic, succinic, tartaric, glucuronic and citric acids as wellas alkyl or arylsulfonic acids, such as p-toluenesulfonic acid,2-naphthalenesulfonic acid, or methanesulfonic acid. Typically suitablepharmaceutically acceptable salts include the following anions: acetate,adipate, besylate (benzenesulfonate), bromide,camsylate[(+)-7,7-dimethyl-2-oxobicyclo[2.2.1]hepatane-1-methanesulfonate],chloride, citrate, edisylate(1,2-ethanedisulfonate), estolate(dodecylsulfate), fumarate, gluceptate(glucoheptonate), gluconate, glucuronate,hippurate, hyclate(hydrochloride, hemiethanolate), hydrobromide,hydrochloride, iodide, isethionate (2-hydroxyethanesulfonate), lactate,lactobionate, maleate, mesylate (methanesulfonate), methylbromide,methylsulfate, napsylate, nitrate, oleate, pamoate[4,4′-methylenebis[3-hydroxy-2-napthalene-carboxylate]], phosphate,polygalacturonate, stearate, succinate, sulfate, sulfosalicylate,tannate, tartrate, terephthalate, tosylate(p-toluenesulfonate),triethiodide.;

[0215] and the following catrons:

[0216] benzathine (N,N-bis(phenylmethyl)-1,2-ethanediamine), calcium,diolamine (2,2-iminobis(ethanol),meglumine[1-deoxy-1-(methylamino)-D-glucitol], olamine(2-aminoethanol),potassium, procaine, sodium tromethamine [2-amino-2-(hydroxymethyl)-1,3propanediol,] and zinc.

[0217] The preferred pharmaceutically acceptable salts aretrifluoroacetate, tosylate, mesylate, and chloride.

[0218] Solid form preparations include powders, tablets, dispersiblegranules, capsules, cachets and suppositories. The powders and tabletsmay be comprised of from about 5 to about 95 percent active ingredient.Suitable solid carriers are known in the art, e.g. magnesium carbonate,magnesium stearate, talc, sugar or lactose. Tablets, powders, cachetsand capsules can be used as solid dosage forms suitable for oraladministration. Examples of pharmaceutically acceptable carriers andmethods of manufacture for various compositions may be found in A.Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition,(1990), Mack Publishing Co., Easton, Pa.

[0219] Liquid form preparations include solutions, suspensions andemulsions. As an example may be mentioned water or water-propyleneglycol solutions for parenteral injection. Solid form preparations maybe converted into liquid preparations shortly before use for either oralor administration. Parenteral forms to be injected intravenously,intramuscularly or subcutaneously are usually in the form of sterilesolutions and may contain tonicity agents (salts or glucose), andbuffers. Opacifiers may be included in oral solutions, suspensions andemulsions. Liquid form preparations may also include solutions forintranasal administration.

[0220] Aerosol preparations suitable for inhalation may includesolutions and solids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g., nitrogen.

[0221] Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

[0222] The compounds of the invention may also be deliverabletransdermally. The transdermal compositions can take the form of creams,lotions, aerosols and/or emulsions and can be included in a transdermalpatch of the matrix or reservoir type as are conventional in the art forthis purpose.

[0223] Preferably, the pharmaceutical preparation is in a unit dosageform. In such form, the preparation is subdivided into suitably sizedunit doses containing appropriate quantities of the active component,e.g., an effective amount to achieve the desired purpose.

[0224] The effective amount or therapeutically effective amount ofactive compound of the present invention (of formulas I-VIII) in a unitdose of preparation may be varied or adjusted from about 1 mg to about1600 mg per day, preferably from about 1 mg to about 1200 mg per day, orabout 300 mg to about 1200 mg per day, more preferably from about 1 mgto about 800 mg per day, or about 400 mg to about 800 mg per day andmost preferably from about 1 mg to about 100 mg per day from about 400mg to about 600 mg per day, in single or divided doses, according to theparticular compound and particular application.

[0225] The actual dosage employed may be varied depending upon therequirements of the patient and the severity of the condition beingtreated. Determination of the proper dosage regimen for a particularsituation is within the skill of the art. For convenience, the totaldaily dosage may be divided and administered in portions during the dayas required.

[0226] The amount and frequency of administration of the compounds ofthe invention and/or the pharmaceutically acceptable salts thereof willbe regulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. The dose of thepreferred compounds of formulas III to VIII should be chosen to providesteady state plasma concentrations of ribavirin in the range of about0.lug/mL to about 100 ug/mL, preferably in the range of about 0.1 ug/mLto about 50 ug/mL, more preferably in the range of about 1 ug/mL toabout 3 ug/mL., and most preferably in the range of about 1.8 ug/mL toabout 2.6 ug/mL. Plasma ribavirin concentrations may be determined usinghigh pressure liquid chromatographic material with tandem massspectrometric detection. The method was validated with respect tolinearity, selectivity, precision, accuracy and has a limit ofquantitation of 50 microg/mL. A typical recommended daily dosage regimenfor oral administration can range from about I mg/kg/day to about 100mg/kg/day, in two to four divided doses. A compound represented by theformula VI

[0227] or a pharmaceutically acceptable salt thereof;

[0228] wherein AA is a natural or unnatural amino acid moietyrepresented by the formulas in Table AA herein below: TABLE AA

[0229] The present invention concerns compounds represented by theformula VII:

[0230] wherein R⁵⁰ is CH₃CH(NH₂)—CO—, CH₃CH₂(CH₃)CHCH(NH₂)—CO— orH₂N(CH₂)₄CH(NH₂)—CO—; or stereoisomers thereof ,or a pharmaceuticallyacceptable salt thereof.

[0231] R may be CH₃CH(NH₂)—CO—, i.e., α-aminopropanoyl, in the form of astereoisomeric mixture, i.e. the DL-form of α-aminopropanoyl—or as oneof the enantiomers ,i.e.,

[0232] the L-form:

[0233] or D-form:

[0234] or mixtures thereof.

[0235] R may be CH₃CH₂(CH₃)CHCH(NH₂)—CO—,i.e.,2-amino-3-methylpentanoyl,

[0236] (a) as a stereoisomeric mixture, i.e., the DL-Form-DL-(−+)erythro-2 -amino-3-methylvaleroyl of the formula:

[0237] or (b) as one of the diastereomers of the formula, i.e.,

[0238] the L-allo-form of the formula:

[0239] [(+)-threo-2-amino-3-methylpentanoyl];

[0240] or the L-form of the formula:

[0241] [L-(+)-amino-3-methylpentanoyl, or(2S,3S)-2--amino-3-methylpentanoyl];

[0242] or mixtures thereof;

[0243] or (c) as one of the diastereomers of the formula:

[0244] [(2R,3S)-2--amino-3-methylpentanoyl]; or

[0245] [(2R,3R)-2--amino-3-methylpentanoyl];

[0246] or mixtures thereof.

[0247] R may be H₂N(CH₂)₄CH(NH₂)—CO— in the form of a stereoisomericmixture, or as one of the enantiomers i.e., the L-form of the formula:

[0248] or,

[0249] the D-form of the formula:

[0250] Preferably, R is L-α-aminopropanoyl of the formula:

General Synthetic Preparation

[0251] Ribavirin, 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide,available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif., isdescribed in the Merck Index, compound No. 8199, Eleventh Edition. Itsmanufacture and formulation is described in U.S. Pat. No. 4,211,771.

[0252] The ribavirin derivatives of formulas I -VIII may be prepared byuse of the sequences of steps illustrated in the following Schemes, andin the Examples using the compounds listed hereinafter the Schemes.

[0253] In Scheme I, compounds of formula I whereinR⁵═R^(5a)CO—,R³═R^(3a)CO and R²═H and R⁵═R^(5a)CO— and R²═R^(2a)CO— andR³═H and R⁵═R^(5a)CO— and R³═R²═H, are prepared. Compound 110(ribavirin) and benzaldehyde are treated with ZnCl₂ in excessbenzaldehyde as solvent at ambient temperature (20 to 25° C.) for 24hrs. to give compound 111. Treatment of 111 with the alkanoyl chlorideR^(5a)COCl in the presence of base e.g. triethylamine (“TEA”); or withthe carboxylic acid (R^(5a)COOH) and triethylamine and coupling reagentsuch as dicyclohexylcarbodiimide (“DCC”) produces compound 112. Removalof the acetal protecting group with trifluoroacetic acid:water (9:1,v/v)at ambient temperature for 0.25-2 hrs, preferably about 0.05 hrs.provides compound 113. Compound 113 is converted into a mixture ofcompounds 114 and 115 by treatment of 113 with R^(3a)COOH, base and DCCor R^(3a)COCl and base, e.g., TEA.

[0254] Compounds 114 and 115 may be separated by standardchromatographic techniques to provide pure compounds 114 and 115.

[0255] In Scheme II, compounds of formula 1 wherein R⁵═R³═H andR²—R^(2a)CO— are prepared from compound 110 (ribavirin). Compound 110 istreated with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane, i.e.,[(i-Pr)₂SiCl]₂0, in DMF as solvent in the presence of imidazole for 1-4hrs. at ambient temperature to give compound 116. Treatment of 116 withR^(2a)CO Cl and base e.g., TEA or R^(2a)COOH, base and a couplingreagent e.g., DCC for 12-48 hrs. at ambient temperature provides 117.Treatment of 17 with Bu₄NF in tetrahydrofuran (“THF”) at ambienttemperature for 1-10 hrs. provides compound 118.

[0256] Scheme III illustrates the preparation of the compounds offormula I wherein R⁵═R²═H and R³═R^(3a)CO— and R⁵═R³═H and R²═R^(2a)CO—Ribavirin is treated with trityl chloride or [MeOC₆H₄(C₆H₅)₂]CCOCl andbase, e.g., pyridine in a solvent DMF at ambient temperature for 6-24hrs. to provide 119. Treatment of 119 with R^(2a)COCl and base orR^(2a)COOH, base and a coupling reagent, e.g., DCC, provides a mixtureof compounds 120 and 121. The mixture is separated into the purecompounds by standard chromatographic techniques. Treatment of 120 or121 with paratoluenesulfonic acid (“p-TsOH”) in methanol in the presenceof hydrogen and a palladium on charcoal catalyst at ambient temperaturefor 2-48 hrs. removes the protecting group to give 122 and 123,respectively. p-TsOH salt thereof.

[0257] Scheme IV illustrates preparation of the compounds of formula Iwherein R⁵═R^(5a)CO— or R⁵═R^(5a) and R³═R²═H. Treatment of ribavirin110 with R^(5a)COON═C(CH₃)₂ in the presence of an enzyme, such as NovoSP 435 lipase at 65° C. in a solvent such as THF or dioxane for 12-48hrs selectively adds R^(5a)CO to the form compound 124. See alsoExamples 9 to 14.

[0258] Reagents: (i) ZnCl₂, PhCHO, (ii) R^(5a)COCl, Et₃N; or R^(5a)COOH,Et₃N, coupling reagent, (iii) TFA-H₂O (9:1), (iv) R^(3a)COOH orR^(3a)(W)_(x)COOH, coupling reagent, base; or R^(3a)COCl, orR^(3a)(W)xCOCl, base, (v) R^(3a)COOH, coupling reagent, base; orR^(3a)COCl, base

[0259] Reagents: (i) [(i-Pr)₂SiCl]₂O, imidazole, DMF; (ii) R^(2a)COCl,base; or R^(2a)COOH, coupling reagent, base; (iii) Bu₄NF, THF

[0260] Reagents: (i) TrCl, base; (ii) R^(2a)COCl, base; or R^(2a)COOH,base, coupling reagent; (iii) TsOH, MeOH, H₂, Pd/C

[0261] Reagents: (i)

[0262] , SP435 lipase, 65° C., THF

[0263] Examples for all schemes:

[0264] R^(2a)CO, R^(3a)CO or R^(5a)CO═

[0265] X=OH, OAc, COCH3, NH2, NHCOCH3, CH2OH, NHCbz, OMe, CN, NO2, F,Cl, Br, (C1-C6)alkyl, e.g. CH3, and disubstituted benzoates with aCombination of these qroups ‘X’.

[0266] (and 5′→3′ cyclic diester)

[0267] R^(2a)CO, R^(3a)CO, and R^(5a)CO may also be represented by theformula:

[0268] Y=H, CH₃; CH₃CH₂—; CH₃CH₂CH₂—; Me₂CH—; Me₂CH₂CH₂—;CH₃CH₂CH(Me)—PhCH₂—; HOOCCH₂CH₂—; HSCH₂—; HOOCCH₂—; MeSCH₂CH₂—; HOCH₂—;

[0269] or Y is H₂N(CH₂)₄— or CH₃CH(OH)—;

[0270] or Y taken together with the α carbon and N form

[0271] or a pharmaceutically acceptable salt thereof.

[0272] Examplary 5′-heteroaryl esters of Formulas I& II wherein R⁵=

[0273] represents a heteroaryl ring of 5-7 total atoms at maximumunsaturation

[0274] wherein: D=C, or when θ>0 is N or S

[0275] E=O or NH

[0276] Z¹ and Z²=independently —C(H)═, —C(H)═N—, —N═, —N(H)—, S, S—C(H)═or S—N═θ and β independently 0, 1, or

[0277] ω and Φ=independently 1, 2, or 3. The 5′-ester of formula isrepresented by the formula:

[0278] The following 5′ esters may be prepared as described in Schemeshereinabive, using appropriately protected acids which are readilyobtained by procedures well known to one skilled in the art.

[0279] D=C, E=NH, Z¹=(—CH═N—), Ω=1, D=C, E=O, Z¹=(—CH═N—), Ω=1, Z²=—NH—,Φ=1, θ=0, and β=0 Z²=—CH═, Φ=2, Φ=0, and β=1

[0280] The folowing 5′-3′ cyclic ester (Formula I wherin R²═H)may beprepared using the Schemes herein above and readily available startingmaterials.

[0281] wherein R¹⁰¹ and R¹⁰² are independently H, alkanoyloxy, OR^(7b)or NR⁶R^(7b) and x=1 or 2

[0282] The following 3′-2′ cyclic esters(formula I wherein R⁵═H) may bemade using the Schemes herein above and readily available startingmaterials.

EXAMPLE I

[0283] A.

[0284] A.-Benzylidene ribavirin

[0285] Combine 20 g ribavirin (1, 87 mmol), 200 ml of benzaldehyde, and20 g of ZnCl₂. Stir the so-formed reaction mixture at ambienttemperature for 24 hours. Pour the resulting solution, with stirring,into 2.5 L of ethyl ether (Et₂O). Suction-filter the resulting mixtureand dry the solid precipitate. Mix the solid precipitate with 1.2 L ofice-cold 2N sodium hydroxide (NaOH) solution. Extract the mixture with2×0.75L of cold ethyl acetate (EtOAc) and wash the organic layer withbrine. Gravity-filter the organic layer through fluted filter paper,then concentrate it in vacuo to leave a solid. Triturate the solidthoroughly with 0.5 L of Et₂O, suction-filter and wash the so-formedpreciptate with fresh Et₂O to leave 23 g of compound 2 as a solid; Calc.for C₁₅H₁₆N₄O₅ (332.32). MS(FAB)=333.1.

[0286] B.

[0287] Combine 0.5g (2.8 mmol) of compound 2 from step A,0.80 g(2.4mmol) of compound 4 [MeO(CH₂CH₂O)₂CH₂CO₂H] and 0.8 g (1.2 mmmol) of4-(N,N,dimethylamino)pyridine (DMAP) in 15 ml of N,N,-dimethylformamide(DMF). Add 2.5 ml of a 1M solution of dicyclohexylcarbodiimide (DCC) indichloromethane (CH₂Cl₂),and stir the resulting mixture at ambienttemperature for 0.5 hour. Heat the so-formed reaction mixture at 100° C.for 1 hour. Quench the reaction mixture with aqueous 5% KH₂PO₄, andextract it with 2×100 ml of ethyl acetate (EtOAc). Wash the organicextract with 20 ml cold water, then with saturated brine. Gravity-filterthe organic extract through fluted filter paper, then concentrate thefiltrate in vacuo to leave a gum residue. Purify the residue by columnchromatography (silica gel, gradient of 1% to 6% methanol-CH₂Cl₂) togive 0.48 g of compound 4; Calc. for C₂₂H₂₈N₄O, (492.49); MS(FAB)=493.1.

[0288] C.

[0289] C.Treat 0.45 g 4 (0.91 mmol) with 10 ml of trifluoroacetic acid(TFA)-water (9:1 v/v) at ambient temperature for 0.5 hour. Quench with30 ml xylene, then concentrate the so-formed mixture in vacuo to leave agum. Triturate the gum with EtOAc, dilute with Et₂O, then suction-filterand dry the gum to leave 0.23 g of compound 5 as a solid, Calc.C₁₅H₂₄N₄O₉ (404.38); MS(FAB)=405.1.

EXAMPLE 2

[0290] Follow the procedures of Example 1A and I B except substitute anequivalent amount of the compound 6 (MeOCH₂CH₂OCHCO₂H) for compound 3 instep B to form compound 8. Follow the procedures of step C of Example 1except substitute an equivalent amount of compound 7 for compound 4 toform the compound 8.

EXAMPLE 3

[0291]

[0292] A.Treat a solution of 0.32 g (3.6 mmol) of compound 9[2-(N,N′-dimethylamino)ethanol] 10 mL of N,N,-dimethylformamide (DMF) at5° C. with 0.58 g carbonyidiimidazole (3.6 mmol), and allow theso-formed solution to warm to 20° C. over 0.5 hr. Add to the resultingreaction mixture 0.8 g (2.4 mmol) of compound 2 prepared in accordancewith Example 1A and stir the so-formed reaction mixture at ambienttemperature for 24 hr. Concentrate the mixture in vacuo, add 50 mL ofethyl ether, and allow the so-formed mixture to set for 24 hr. Decantthe supernatant solution, and purify the residue by columnchromatography (silica gel, gradient of 10% to 20%methanol-tetrahydrofuran) to give 0.21 g of compound 10; calc.C₂₀H₂₅N₅O₇ (447.44). MS(FAB)=448.1.

[0293] B.

[0294] Follow the procedures of Example 1C except substitute anequivalent amount of compound 10 for compound 4 to obtain compound 11.

EXAMPLE 4

[0295] A.

[0296] A stirred, dry DMF (5m L) solution of 500 mg (1.506 mmol) ofcompound 2 prepared in accordance with the procedures of Example I A,300 mg (1.2 eq) of piperonylic acid (compound 12) was treated at ambienttemperature with 732 mg (1. 1 eq) ofbenzotriazolyloxytris-(dimethylamino)phosphonium hexafluorophosphate(“BOP reagent”) and 576 μL (2.2 eq) of Hunig's base, i.e.,-diisopropylethyl amine, [(i-Pr)₂NEt], under a nitrogen atmosphere. Theso-formed reaction mixture was stirred overnight at ambient temperature.Thin layer chromatography (TLC) showed one major new spot. The reactionmixture was quenched with an aqueous NH₄Cl solution and diluted withEtOAc. The organic layer was washed with water and brine and then driedover Na₂SO₄. The organic solvent was evaporated to produce a crudepurple solid. The crude solid was purified on a silica gelchromatography column with 2-3% MeOH/CH₂Cl₂ as an eluent. Theappropriate fractions were combined to give 550 mg of compound 13 as apurple-tinted solid (76% yield). The 'H nmr spectrum (350 MHz in CDCl₃)was consistent with the structure of 13.

[0297] B.

[0298] Compound 13 from step A was treated with 4 mL of TFA:H₂O (9:1,v/v) for 40 min. at ambient temperature. The solvents were evaporatedto give a yellow solid. Water was added and evaporated. The crude solidwas dried overnight. To the crude product was added 2×4 mL of MeOH. TheMeOH layer was yellow. The insoluble material was collected and dried togive 342 mg of compound 14 as a white solid. The 'H nmr spectrum wasconsistent with the structure of 14.

EXAMPLE 5

[0299] A.

[0300] To a stirred solution of 500 mg (1.505 mmol) of 2 prepared inaccordance with Example 1A in 3 mL of dry DMF at ambient temperature wasadded 516 mg (1.2 eq) of stearic acid (compound 15), 670 mg (1.0 eq) ofthe BOP reagent and 792 μL (3.0 eq) of Hunig's base. The so-formedreaction mixture was stirred overnight at ambient temperature. Thereaction mixture was isolated in accordance with the procedures ofExample 4A to give 595.5 mg of compound 16 as a viscous white solid (66%yield). The 'H nmr spectrum was consistent with the structure of 16.

[0301] B.

[0302] Compound 16 (417 mg, 0697 m mol) was treated in accordance withthe procedures of Example 4B to give 330 mg of compound 17 as a whitesolid (93% yield). The 'H nmr spectrum and MS-FAB were consistent withthe structure of 17.

EXAMPLE 6

[0303] A.

[0304] To a stirred suspension of 332 mg (1.0 mmol) of compound 2prepared in accordance with Example 1A in 5 ml of dry CH₂Cl₂ was added209 μL (1.5 eq) of triethylamine (Et₃N) and 167 μL (1.2 eq) of o-toluoylchloride (compound18). TLC showed completion of the reaction after thereaction mixture had been stirred at ambient temperature for 4 hours.The so-formed clear reaction mixture was diluted with EtOAc and quenchedwith water. The separated organic layer was washed with water and brine,dried and evaporated to give a crude white solid. The crude solid waspurified on silica gel column chromatography elueting with 2-3% MeOH togive 262 mg of compound 19 as a white solid (57% yield).

[0305] B.

[0306] Compound 19 (262 mg) was treated with 3 mL of TFA:H₂O (9:1 v/v)in accordance with the procedure of Example 4A to give 210 mg (99%yield) of the compound 20. The 'H nmr spectrum was consistent with thestructure of compound 20.

EXAMPLE 7

[0307] A.

[0308] To a stirred suspension in a reaction flask immersed in an icebath of 498 mg (1.5 m mol) of 2 prepared in accordance with Example 1Ain 10 mL of dry CH₂C1₂ was added 146 μL (1.80 mmol, 1.2 eq) of pyridineand 203 μL (1.65 mmol, 1.1 eq) of trimethylacetyl chloride (compound 21)at 0° C. The ice bath was removed after 5 min. Stirring was continuedfor 30 min. and 1 mL of DMF was added; the mixture changed from asuspension to a cloudy solution. By TLC, there was a substantial amountof unreacted starting material (compound 2). The reaction mixture wasstirred overnight, and an additional amount of compound 21(203 μL,1.1eq) and 180 mg (1.5 eq) of DMAP were added. The so-formed reactionmixture was stirred for 4 days at ambient temperature. There was stillsome unreacted starting material(compound2) by TLC. The reaction mixturewas worked-up by routine extraction between H₂O/EtOAc. The crude productwas purified by silica gel column chromatography eluting with 2-5%MeOH/CH₂Cl₂ to give 411.3 mg of compound 22 (66% yield) as a whitesolid.

[0309] B.

[0310] Compound 22 (316 mg) was treated with 4 mL of TFA:H₂O (9:1 v/v)in accordance with the procedures of Example 4B to give 265 mg ofcompound 23.

EXAMPLE 8

[0311] A.

[0312] To a stirred mixture of 500 mg (2.1 m mol) of ribavirin and 2.07g (1.04 mL, 1.5 eg, 3.1 mmol) of N,N-disopropyl-dibenzyl phosphoramidein 5 mL of DMF at room temperature, was added 433 mg (6.1 m mol, 3 eq)of tetrazole. The resulting reaction mixture was stirred at roomtemperature for 2 hrs., and then 1.11 mL (3 eq) of tert-butylperoxide(5.5M in decane) were added. The so-formed reaction mixture was stirredfor 2 hrs. Water was added and the organic layer was washed, dried andevaporated to give a crude product. The crude product was purified onsilica gel column chromatography using MeOH/CH₂Cl₂ as an eluent to give493 mg of compound 24 as white solid. FAB:MS:MH⁺=505.2.

[0313] B.

[0314] A suspension of compound 24 (278 mg) in a mixture of 3 mL of MeOHand 3 mL of water and 150 mg of 10% Pd on carbon was placed under anatmosphere of hydrogen for 4 hrs. The suspension was filtered through apad of celite and the solid was washed thoroughly with MeOH. Thecombined filtrates were concentrated under reduced pressure to give169.3 mg of the compound 25 as a white solid. FAB-MS, MH⁺=325.1

EXAMPLE 9

[0315] A.

[0316] An oil dispersion of NaH (0.88 g of NaH, 0.022 mmol, 1.1 eq) waswashed once with dry hexane and then suspended in 10 mL of dry THF.Compound 26 (N-phenylpiperazine, 3.24 g, 20 mmol) was added to thereaction vessel containing NaH in dry THF immersed in an ice bath Theice bath was removed and the so-formed reaction mixture was stirred for1 hr. at room temperature. To the stirred white reaction mixture wasadded 2.66 mL (0.024 m mol, 1.2 eq) of ethyl bromoacetate. The so-formedreaction mixture was stirred overnight. The reaction mixture was cooledto ice bath temperatuare and quenched with an aqueous NH₄Cl solution.The so-formed mixture was extracted with EtOAc and the organic layer waswashed with aqueous NH₄Cl brine and dried. The solvent was removed atreduced pressure to provide a crude product which was purified on asilica gel chromatography column using 20% EtOAc/hexane (v/v) as aneluent to provide 2.10 g of compound 27 (ethyl N-phenylpiperazinylaceticacid) as a clear oil. The 'H nmr spectrum was consistent with thestructure of compound 27.

[0317] B.

[0318] To a stirred solution of 2.10 g (8.47 m mol) of compound 27 in8.47 mL of MeOH was added 8.47 mL (1.0 eq) of a 1 N NaOH solution. Theso-formed reaction mixture was stirred for 3 hrs. at room temperature(no compound 27 was found by TLC). The solvents were removed underreduced pressure to provide a crude product. Water was added to thecrude product and the solution was freeze dried overnight to provide2.10 g of compound 28 as a white solid. The 'H nmr spectrum wasconsistent with the structure of compound 28.

[0319] C.

[0320] To a stirred solution of 1.21 g (5.0 m mol) of compound 28 in amixture of 15 mL of CH₃CN and 5 mL of DMF was added 1.146 g (6.0 m mol,1.2 eq) of EDC. HCl followed by 837 μL (6.0 m mol, 1.2 eq) of Et₃N and731 mg (10.0 mmol, 2 eq) of acetone oxime (compound 28). The so-formedreaction mixture was stirred overnight and then diluted with EtOAc. Theorganic layer was washed with water and brine, dried and concentrated togive a crude product. The crude product was purified on silica gelcolumn chromatography using 20% EtOAc/hexane (v/v) as an eluant to give237 mg of compound 29 as a white solid. The 'H nmr spectrum of the oximeester was consistent with the structure of compound 29.

[0321] D.

[0322] A suspension of 105.0 mg (0.431 m mol) of ribavirin 237 mg (0.862m mol) of oxime ester 29 and 0.1 g of Novo SP435 lipase (Candidaantarctica) in 5 mL of anhydrous THF was stirred at 65° C. for 24 hrs.The so-formed reaction mixture was cooled to room temperature, filteredand washed with MeOH. The crude material was purified on silica gelcolumn chromatography using 10% MeOH/CH₂Cl₂ (v/v) as eleunt to produce66 mg of Compound 30 (a white solid) as a single product (in 42% yield).No other product was observed by TLC. The 'H nmr spectrum (300 MHz,DMSO-d₆) was conistent with the 5′ ribavirin ester of structure 30.

EXAMPLE 10

[0323] A.

[0324] To a stirred solution of 2.45 g (1.4 mmol) of hippuric acid(compound 31) and 1.00 g (1.0 eq) of acetone oxime in 10 mL of CH₂Cl₂ atroom temperatuare was added 2.83 g (1.0 eq) of DCC. The so-formedreaction mixture was stirred overnight and then filtered. The filtratewas concentrated under reduced pressure to produce a residue which waspurified with EtOAc/hexane to give 2.36 g of the acetone oxine ester(32) as a colorless oil. The FAB-MS: MH⁺=235.1.

[0325] B.

[0326] The procedure of Example 9, Step D was used except 2.13 g (9mmol) of compound 32 was substituted for compound 29, 0.734 g (3 mmol,⅓eq) of ribavirin and 0.6 g of SP435 lipase were used in 25 ml of THF.The crude product was purified on silica gel column chromatography usingCH₂Cl₂:MeOH (20:1, v/v) as an eluent to provide a crude product. Thecrude product was crystallized from MeOH:Et₂O to provide 0.936 g ofcompound 33. FAB:MS, MH⁺=406.1.

EXAMPLE 11

[0327] A.

[0328] Compound 34 , the acetone oxime ester of Cbz-L-alanine, wasprepared in accordance with the procedures of F.Morris and V. Gotor,Tetrahedron, 1994, 50, 69-6934 at paragraph bridging 6932-6933.. Then,the procedure of Example 10, Step B, was followed using 1.00 g (3.6mmol) of compound 34 in place of compound 32, 0.294 g (1.2 mmol) ofribavirin, and 0.48 g of Novo SP435 lipase in 12 ml of THF. The crudeproduce was purified on silica gel column chromatography usingCH₂Cl₂:MeOH (20:1, v/v) as an eleunt to give 0.660 g of compound 35 as awhite solid. The white solid was recrystallized from MeOH-EtOAc to give0.532 g of compound 35.

[0329] C.

[0330] To a mixture of 0.100 g (0.222 mmol) of compound 35 and 42.3 mg(1 eq) of TSOH.H₂O in 3 ml of aqueous MEOH was added 50 mg of 10% Pd oncarbon. The resulting black suspension was placed under a hydrogenatmosphere for 4 hours. The so-formed reaction mixture was filteredthrough a pad of celite and the solid was washed thoroughly withmethanol. The combined filtrates were concentrated and the solventremoved to give 0.101 g of compound 36 as a white solid. FAB:MSMH⁺=316.1.

EXAMPLE 12

[0331] A.

[0332] Compound 38 (PhCH₂OCH₂COO—N═C(CH₃)₂) was prepared from 2.17 ml(2.53 eq) benzyloxyacetylchloride (Compound 37) and 1.00 g of acetoneoxine in 20 ml of CH₂Cl₂ containing 1.67 g (1 eq) of DMAP in accordancewith the procedure of Example 10 Step A. Then, the procedure of Example10, Step B was followed using 2.40 g (10.8 mmol) of compound 38 in placeof compound 32 1.325 g (5.4 mmol) of ribavirin 2.18 g of Novo SP435lipase in 70 ml of THF. The mixture was treated overnight at 70° C.under a nitrogen atmosphere. The crude product was purified on silicagel column chromatography using CH₂Cl₂:MeOH (10:1, v/v) as an eluent toprovide 0.511 g of a mixture of two compounds. The desired compound 39was purified by crystallization from MeOH:Et₂O to give 0.367 g ofcompound 39 as a white crystalline product.

[0333] B.

[0334] To a stirred suspension of 0.200 g of compound 39 in 5 ml of MeOHcontaining 50 mg of palladium black under an atmosphere of nitrogen wasadded 0.20 ml of formic acid. The resulting reaction mixture was heatedto reflex for 1 hour. The resulting reaction mixture was cooled andfiltered through a pad of cotton wool. The solids were thoroughly washedwith methanol and then water. The combined filtrates were concentratedunder reduced pressure to give a residue. Methanol was added to provide99.2 mg of the compound 40. FAB-MS:MH⁺=303.1.

EXAMPLE 13

[0335]

[0336] Compound 40 (PhCH₂OCOO—N═C(CH₃) was prepared in accordance withthe procedure of Step A of Example 10. Then the procedure of Step B ofExample 10 as followed using 500 mg (2.4 mmol) of compound 40 in placeof compound 32, 295 mg (1.2 mmol) of ribavirin, 160 mg of Novo SP435 in15 ml of THF. The so-formed reaction mixture was heated at 70° C. for 3days. The crude product dissolved in MeOH was purified on silica gelcolumn chromatography using CH₂Cl₂:MeOH (20:1, v/v) as an eleunt toprovide 156 mg of compound 41. FAB:MS, MH⁺=379.2.

EXAMPLE 14

[0337] A. The benzyl ether of methyl-L-lactate (compound 42) wasprepared from methyl-L-lactate in accordance with the procedures of U.Widner Synthesis 1987, 568.

[0338] B.

[0339] To a stirred solution of 1.00 g of compound 42 in a mixture of 9ml of MeOH and 3 ml of water was added 216 mg (1 eq) of LiOH.H₂O. Theso-formed reaction mixture was stirred for 4 hours. The resultingmixture was partitioned between CH₂Cl₂ and water. The aqueous phase wasseparated, washed with CH₂C₂ and acidified with excess 10% aqueous HCl.The organics were extracted with EtOAc. The EtOAc layer was dried andconcentrated to give 779 mg of compound 43 as a colorless oil.

[0340] C.

[0341] The procedures of Step A of Example 10 were followed using 1.15 g(6.39 mmol) of compound 43 in place of compound 31, 513 mg, (7.03 mmol,1.1 eq) of acetone oxime, 1.45 g of DCC in 5 ml of CH₂Cl₂ to produce1.20 g of the acetone oxime ester, compound 44.

[0342] D.

[0343] The procedure of Step B of Example 10 was followed using 1.2 g(5.1 mmol) of compound 44 in place of compound 32, 600 mg (2.5 mmol) ofribavirin and 500 mg of Novo SP435 lipase in 20 ml of THF. The mixturewashed at 700C until no starting found by TLC.

[0344] The crude reaction product was purified by silica gel columnchromatography using CH₂Cl₂:MeOH (20:1, v/v) to produce 183 mg ofcompound 45 as a white solid.

EXAMPLE 15

[0345]

[0346] A solution of N-t-Boc-L-isoleucine (available fromsigma ChemicalCo. St. Louis, Mo.) (1.270 g, 5.5 mmol) in anhydrous THF (30 mL) wastreated with CDI, i.e., carbonyl-diimidazole (981 mg, 6.05 mmol) at roomtemperature for 1 hr. The compound 2 of Example 1 (1.660 g, 5.00 mmol)and sodium imidazolide (150 mg, 1.5 mmol) were then added to thereaction mixture. This mixture was heated at 45° C. for 20 hrs. Thereaction was diluted with EtOAc and quenched with aqueous NH₄Cl. Theorganic layer was washed with water three times and once with brine, anddried over Na₂SO₄ The dried organic layer was filtered and the filtratewas concentrated to give an off white solid which was purified on silicagel column chromatography (5-10% by volume of MeOH in CH₂Cl₂) to afford1.244 g of compound 47.

[0347] Compound 47 was treated with trifluoroacetic acid (TFA)/ water(9:1 v/v) at room temperature for 1 hr. All volatiles were evaporated.Water was added and evaporated again to afford 1.10 g of compound 48 asa soft solid. MS(FAB)=358 (MH⁺, 100%).

EXAMPLE 16

[0348]

[0349] A solution of N,N-diCbz-L-lysine (available fromSigma ChemicalCo. St. Louis, Mo.) (749 mg, 1.81 mmol) and compound 2 (500 mg, 1.506mmol) in anhydrous DMF (5 mL) was treated with (732 mg, 1.66 mmol) ofbenzotriazolyloxytris-(dimethylamino)phosphonium hexafluorophosphate(“BOP reagent” available fromsigma Chemical Co. St. Louis, Mo.) followedby 576 mL, 3.31 mmol of Hunig's base, i.e., N,N-diisopropyl-ethyl amine,[“(i-Pr)₂NEt” available from Aldrich Chemical Co., Milwaukee, Wis.]under a nitrogen atmosphere at room temperature. The reaction mixturewas is stirred at room temperature overnight. The reaction mixture wasdiluted with EtOAc and quenched with aqueous NH₄Cl. The organic layerwas washed three times with water, once with brine, and dried overNa₂SO₄ and . The dried organic layer was filtered and the filtrate wasconcentrated to give compound 49 as an off white solid .

[0350] Compound 49 was treated with trifluoroacetic acid/ water (9:1v/v) at room temperature for 1 hr. All volatiles were evaporated. Waterwas added and evaporated again to afford the crude product which waspurified on a silica gel column (10 % by volume of MeOH in CH₂Cl₂ ) toafford 520 mg of compound 50 as a white solid.

[0351] A solution containing compound 50(140 mg, 0.219 mmol) andp-toluenesulfonic acid monohydrate, TsOH H₂O (83 mg, 0.438 mmol) washydrogenated over 10% Pd/C (50 mg) under H₂ at a pressure of 1 atm for 4hr. The catalyst was filtered off through a bed of Celite and washedwith methanol-water. The filtrate was evaporated to afford 157 mg ofcompound 51 as a white powder. MS(FAB)=373 (MH⁺, 100%).

EXAMPLE 17

[0352] Follow the procedures of Examples 11, 15 or 16 except substitutean equivalent amount of the Cbz- or Boc-D-amino acid derivative of theamino acid listed in the left hand column in the Table 3 below for theBoc-L-isoleucine used in Example 15, or the diCbz-L-lysine used inExample 16, or the Cbz-L-alanine used in Example 11 to obtain thecompounds of formula I or a pharmaceutical accepable salt thereofwherein the R is the moiety listed in the right hand column of the Table4 below. TABLE 4 COLUMN A COLUMN B

[0353] Many modifications and variations of this invention can be madewithout departing from its spirit and scope, as will be apparent tothose skilled in the art. The specific embodiments described herein areoffered by way of example only, and the invention is to be limited onlyby the terms of the appended claims, along with the full scope ofequivalents to which such claims are entitled.

1. A compound represented by formula II

wherein at least one of R^(2′), R^(3′) or R^(5′) is H, R²⁰-(W)_(x)-CO—,R²⁰-(W)_(x)-CS— or R²⁰-(W)_(x)-PO(OH)—; and wherein at least one ofR^(2′),R^(3′) or R^(5′) is not H; wherein R²⁰ is alkyl, H, alkanoyl,cycloalkyl, aryl, heterocyclic, NR²¹R²², alkenyl, or alkynyl; or isalkyl, alkanoyl alkenyl or alkynyl substituted by halo, phenyl,cycloalkyl, NR²¹R²², hydroxy, alkoxy; or is aryl substituted by phenylhalo, CN, NO₂, OH, R²⁸, OR²⁸, CF₃, SH SR²¹, SOR²¹, SO₂R²¹; NR²¹R²² CO₂H,CO₂ ⁻, OR²¹, O⁻M⁺ or S⁻M⁺; wherein M⁺ is an alkali metal cation; or R²⁰is —(CHR²¹)_(e)—(CH₂)_(f)—CO—OR²², —(CHR²¹)_(e)—(CH₂)_(f)—OR²², or—(CHR²¹)_(e)—(CH₂)_(f)—NR²¹R²² W is O, NR²⁸ or S; R²¹ is H, alkyl,alkanoyl, Y or aryl or is alkyl, alkanoyl or aryl suabstituted by halo,phenyl, CN, NO₂ OH, CO₂H or alkoxy; and R²² is H, alkyl or aryl or isalkyl or aryl substituted by phenyl; halo, CN, NO₂, OH, CO₂H or alkoxy;or R²¹ and R²² taken together with N and one of CHR²¹ , NR²¹, O, S, SOor SO₂ form a five-, six- or seven- membered ring; R²⁷ is H, OR²¹,NR²¹R²², R²⁰-(W)_(x)-CO—, R²⁰-(W)_(x)-CS—, (HO)₂PO— orR²⁰-(W)_(x)-PO(OH)— or HO—SO₂—; R²⁸ is H, alkanoyl, aryl, alkyl or alkylsubstituted by OH, halo or NR²¹R²²; e=0 to 6, f=0 to 10, t=0 to 100; s=0to 6000; r=1 to 5000; and x=0 or 1; or a pharmaceutically acceptablesalt thereof.
 2. A pharmaceutical composition of a compound of claim Ior a pharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier.
 3. A method of using a compoundrepresented by formula II of claim 1 for treating a susceptible viralinfection , wherein the method comprises a therapeutically effectiveamount of a ribavirin derivative of formula II of claim 1 or apharmaceutically acceptable salt thereof.
 4. A method of using acompound represented by formula II of claim 1 in association withinterferon alpha for treating a chronic hepatitis C infection , whereinthe method comprises a therapeutically effective amount of a ribavirinderivative of formula II of claim 1 or a pharmaceutically acceptablesalt thereof and a therapeutically effective amount of an interferonalpha.
 5. The method of claim 4, wherein the interferon-alpha isselected from interferon alpha-2a, interferon alpha-2b, a consensusinterferon, a purified interferon alpha product or a pegylatedinterferon-alpha-2a, pegylated interferon-alpha-2b, pegylated consensusinterferon.
 6. The method of claim 4, wherein the interferon-alphaadministered is a pegylated interferon alpha-2b and the amount ofpegylated interferon-alpha-2b administered is from 0.5 to 2.0micrograms/kilogram per week on a weekly, TIW, QOD or daily basis, 7.The method of claim 4, wherein the interferon-alpha administered is apegylated interferon alpha-2a and the amount of pegylated interferonalpha-2a administered is from 20 to 250 micrograms per week on a weekly,TIW, QOD or daily basis.
 9. The compound of formula II of claim 1,wherein R^(2′)=R^(3′)=H.
 10. The compound of formula II of claim 1wherein R^(2′)=R^(5′)=H,
 11. The compound of formula II of claim 1wherein R^(3′)=R^(5′)=H.
 12. The compound of formula II of claim 1,wherein R^(5′) is one of

wherein X is independently OH, alkanoyl, amino, alkylamino,dialkylamino, alkanoylamino, hydroxyalkyl, alkoxy, alkyl, CN, NO₂, halo,or alkyl substituted by OH, alkanoyl, amino, alkylamino, dialkylamino ,alkanoylamino, hydroxyalkyl, alkoxy, CN, NO₂, or halo.
 13. The compoundof formula II of claim 1, wherein R^(5′) is

wherein X is OH, COCH₃, OCOCH₃, NO₂, NH₂, [CH₃]₂N, NHCOCH₃, CH₂OH, CH₃,OCH₃, F, Br or Cl.
 14. The compound of claim 1, wherein R^(5′) is


15. A method of treating patients having chronic hepatitis C infectioncomprising administering a therapeutically effective amount of aribavirin derivative of formula I and a therapeutically effective amountof interferon-alpha for a time period sufficient to eradicate detectableHCV-RNA at the end of said period of administering and to have nodetectable HCV-RNA for at least 24 weeks after the end of said period ofadministrating, and wherein the ribavirin derivative is represented byformula l:

wherein at least one of R², R³ or R⁵ is H, R⁶-(W)_(x)-CO—,R⁶-(W)_(x)-CS—(HO)₂PO—,R⁶-(W)_(x)-PO(OH)— or HO—SO₂— and wherein atleast one of R², R³ or R⁵ is not H; wherein R⁶ is H, alkyl, alkanoyl,cycloalkyl, heterocylic, aryl, NR^(7a)R^(7b), alkenyl, or alkynyl; or isalkyl, alkanoyl, alkenyl or alkynyl substituted by halo, phenyl,cycloalkyl, NR^(7a)R^(7b), hydroxy or alkoxy; or R⁶ is aryl substitutedby phenyl, halo, CN, NO₂, OH, R¹⁸,OR¹⁸, CF₃, SHSR^(7a),SOR^(7a),SO₂R^(7a); NR^(7a)R^(7b)CO₂H, CO₂ ⁻M⁺⁻,O⁻M⁺OR^(7a) orS⁻M⁺; wherein M⁺ is an alkali metal cation; or R⁶ is—(CHR^(7a))_(e)—(CH₂)_(f)—CO—OR^(7b), —(CHR^(7a))_(e)—(CH₂)_(f)—OR^(7b),or —(CHR^(7a))_(e)—(CH₂)_(f)—NR^(7a)NR^(7b) W is O, NR⁸ or S; R^(7a) isH, alkyl, alkanoyl, aryl or is alkyl, alkanoyl or aryl substituted byhalo phenyl CN, NO₂, OH, CO₂H or alkoxy; and R^(7b) is H, alkyl or arylor is alkyl or aryl substituted by halo, CN, NO₂, CO₂H, OH or alkoxy; orR^(7a) and R^(7b) taken together with N and one of CHR^(7a), NR^(7a), O,S, SO or SO₂ form a five-, six- or seven- membered ring; R¹⁷ is H,OR^(7a), NR^(7a)R^(7b), R⁶-(W)_(x)-CO—, R⁶-(W)_(x)-CS—, (HO)₂PO—,R⁶-(W)_(x)-PO(OH)—, or HO—SO₂—; R¹⁸is H, aryl, alkyl, or alkylsubstituted by OH, halo, NR^(7a)R^(7b), or alkanoyl; e=0 to 6, f=0 to10, and x=0 or 1; or a pharmaceutically acceptable salt thereof.
 16. Themethod of claim 15 wherein R⁵ is R⁶ CO wherein R⁶ is aryl substituted byphenyl, halo, CN, NO₂, OH, R¹⁸, CF₃, SH SR^(7a), SOR^(7a), SO₂R^(7a);NR^(7a)R^(7b)CO₂H, CO₂ ⁻M⁺, O⁻M⁺OR^(7a) or S⁻M⁺ and wherein M⁺ is analkali metal cation.
 17. The method of claim 15 wherein R⁵ is R⁶COwherein R⁶ is phenyl substituted by, halo, CN, NO₂, OH, R¹⁸, OR¹⁸, CF₃,SH SR^(7a), SOR^(7a),SO₂R^(7a); NR^(7a)R^(7b) CO₂H, CO₂ ⁻M⁺⁻,O⁻M⁺OR^(7a) or S⁻M⁺ and wherein M⁺ is an alkali metal cation.